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It has previously been shown that rats do not expel a primary infection of Nippostronglus brasiliensis during lactation. In the present paper, three aspects of the immune response of the lactating rat to the parasite were examined and compared with the response of non-lactating rats. Protective and reaginic antibodies were present in the circulation of rats first infected during lactation, in titres as high or higher than those in non-lactating controls. The intestinal mast cell response was similar both in timing and magnitude and lactating rats became susceptible to shock with the i.v. injection of antigen. Attention was drawn to the similarity between the response of the lactating rat and that of the neonate to this infection. [ABSTRACT FROM AUTHOR]

As perhaps the staunchest advocates of repertoire purging as the central mechanism of immunological tolerance, we note with satisfaction a spate of recent, elegant papers which suggest an intrathymic clonal abortion model as the explanation for at least some examples of T-cell tolerance. This view agrees with the classical formulation of the Billingham-Brent-Medawar school of tolerance as a specific, central failure of immune responsiveness. Repertoire purging within the B-lymphocyte compartment remains much more controversial. There is no doubt that experimental models exist where the B cell is the reversible target of tolerance induction. The question is, in view of the ease of inducing autoantibody formation both in vivo and in vitro, just how relevant are such clonal anergy mechanisms to authentic self-tolerance? Arguments are presented that there must be two windows of tolerance susceptibility in the ontogeny of the B cell; one while it is maturing in the bone marrow, to prevent autoreactivity of high affinity to important accessible self-antigens; and a second soon after activation of pre-memory cells by exogenous antigen, to prevent fortuitous mutations towards high-affinity anti-self-reactivity establishing a forbidden clone. [ABSTRACT FROM AUTHOR]

T cell inhibitory receptors can regulate the proliferation or function of T cells by binding to their ligands and present a unique opportunity to manage destructive immune responses during porcine islet xenotransplantation. We applied ex vivo porcine islet xenotransplantation and in vitro mixed lymphocyte‐islet reaction models to assess immune checkpoint receptor expression profiles in recipient T cells, investigated whether CTLA4 or VISTA immunoglobulin (Ig) combination therapy alone could suppress porcine islet xenograft rejection and further analyzed its potential immune tolerance mechanism. Recipient T cells expressed moderate to high levels of CTLA4, PD‐1, TIGIT and VISTA, and the frequency of CTLA4+CD4+, TIGIT+CD4+, VISTA+CD4+ and VISTA+CD8+ T cells was positively correlated with porcine islet xenograft survival time in xenotransplant recipients. Combined treatment with CTLA4Ig and VISTAIg selectively inhibited recipient CD4+ T cell hyper‐responsiveness and proinflammatory cytokine production and significantly delayed xenograft rejection. SOCS1 deficiency in CD4+ T cells stimulated by xenogeneic islets facilitated hyper‐responsiveness and abolished the suppressive effect of combination therapy on recipient T cell‐mediated porcine islet damage in vivo and in vitro. Further mechanistic studies revealed that combined treatment significantly induced SOCS1 expression and inhibited the Jak‐STAT signalling pathway in wild‐type recipient CD4+ T cells stimulated by xenogeneic islets, whereas SOCS1 deficiency resulted in Jak‐STAT signalling pathway activation in recipient CD4+ T cells. We demonstrated a major role for CTLA4 and VISTA as key targets in CD4+ T cell hyper‐responsiveness and porcine islet xenograft rejection. The selective inhibition of CD4+ T cell immunity by CTLA4Ig/VISTAIg is based on SOCS1‐dependent signalling. [ABSTRACT FROM AUTHOR]

The concept of immunological tolerance - the state of specific unresponsiveness to allogeneic transplants and all manner of other antigens - began in 1945 with R.D. Owen's finding that cattle dizygotic twins are red blood cell chimeras. Peter Medawar's group in Birmingham likewise discovered, quite independently, that cattle dizygotic twins accept each others' skin grafts. These findings, together with F.M. Burnet and F. Fenner's speculations in 1949, prompted Medawar, together with R.E. Billingham and L. Brent, now at University College London, to embark on an extensive series of experiments that established immunological tolerance as a fundamental phenomenon, forming a new branch of immunology. [ABSTRACT FROM AUTHOR]

Double‐negative (DN) T cells are present at relatively low frequencies in human peripheral blood, and are characterized as expressing the alpha‐beta or gamma‐delta T‐cell receptor (TCR), but not the CD4 nor the CD8 co‐receptors. Despite their low frequencies, these cells are potent producers of cytokines and, thus, are key orchestrators of immune responses. DN T cells were initially associated with induction of peripheral immunological tolerance and immunomodulatory activities related to disease prevention. However, other studies demonstrated that these cells can also display effector functions associated with pathology development. This apparent contradiction highlighted the heterogeneity of the DN T‐cell population. Here, we review phenotypic and functional characteristics of DN T cells, emphasizing their role in human diseases. The need for developing biomarkers to facilitate the translation of studies from animal models to humans will also be discussed. Finally, we will examine DN T cells as promising therapeutic targets to prevent or inhibit human disease development. [ABSTRACT FROM AUTHOR]

The mechanism of generation of regulatory T cells (Treg) remains incompletely understood. Recent studies show that CD83 has immune regulatory functions. This study aims to investigate the role of epithelial cell‐derived CD83 in the restoration of immune tolerance in the airway mucosa by inducing the Treg differentiation. In this study, CD83 and ovalbumin (OVA)‐carrying exosomes were generated from airway epithelial cells. An airway allergy mouse model was developed to test the role of CD83/OVA‐carrying exosomes in the suppression of airway allergy by inducing Treg generation. We observed that mouse airway epithelial cells expressed CD83 that could be up‐regulated by CD40 ligand. The CD83 deficiency in epithelial cells retarded the Treg generation in the airway mucosa. CD83 up‐regulated transforming growth factor‐β‐inducible early gene 1 expression in CD4+ T cells to promote Foxp3 expression. Exposure of primed CD4+ T cells to CD83/OVA‐carrying exosomes promoted antigen‐specific Treg generation. Administration of CD83/OVA‐carrying exosomes inhibited experimental airway allergic response. In summary, airway epithelial cells express CD83 that is required in the Treg differentiation in the airway mucosa. Administration of CD83/OVA‐carrying exosomes can inhibit airway allergy that has the translation potential in the treatment of airway allergic disorders. [ABSTRACT FROM AUTHOR]

A positive association has been observed in Igh allotype ‘congenic’ mice between skin graft rejection and a block to effective T-B co-operation in the development of both IgM and IgG responses to sheep erythrocytes. Mismatch of Igh alone is insufficient for such a block to become apparent since pairs of Igh-allotype congenic strains of mice which reciprocally accept skin grafts for at least 5 weeks, show successful positive co-operation (help) between T and B cells. The observed block is manifest both during the education (priming) of T cells in irradiated (first stage) recipients and during co-operation between primed T cells and unprimed B cells in second stage irradiated ‘syngeneic’ recipients. [ABSTRACT FROM AUTHOR]

A highly purified preparation of double-stranded RNA, obtained from virus-like particles in Penicllium cultures, was found to affect humoral immune responses in mice differentially depending on its time of administration in relation to antigen. Double-stranded RNA administered with antigen, or a few hours after antigen, produced a variable degree of enhancement of plaque-forming cell numbers or agglutinating antibody levels depending on the antigen involved. Administration of double-stranded RNA 24 hours before antigen invariably produced a suppressed response. In mice which were either specifically byporesponsive (tolerant) or non-specifically hyporesponsive (due to age or immunosuppressive drags) double-stranded RNA administered with antigen resulted in a nearly normal immune response. [ABSTRACT FROM AUTHOR]

Bone marrow cells and thymus cells were observed in cell transfer expehments to collaborate in the production of anti-BSA antibodies. The target cells for tolerance induction either with a 'low dose' of antigen (100 µg of deaggregated BSA once a week × 5) or with a 'high dose' (a single injection of 5000 µg) were identified by the same technique. In 'low dose' tolerance, some indication was obtained that thymus-derived cells in peripheral lymphoid systems were the target cells; bone marrow-derived cells appeared not to be so susceptible, and the cells residing in thymus or bone marrow seemed to remain unimpaired, in contrast, the injection of a 'high dose' of tolerogen rendered both types of cells in spleen, thymus cells and bone marrow cells, unresponsive or hyporesponsive in parallel with one another. [ABSTRACT FROM AUTHOR]

Free immunosuppressive antibody is frequently demonstrable in the sera of mice for some days after the completion of a course of ALS. The potency of the immunosuppressive material which is present and the duration for which it remains in the circulation varies according to the ALS used. These two factors appear to be of major importance in determining the rate at which immunological competence is restored to an ALS-treated animal. Recovery is retarded by the presence of free immunosuppressive antibody in the circulation and the degree of retardation is directly proportional to the potency of the material present and the duration for which it remains in the circulation. [ABSTRACT FROM AUTHOR]

A state of immunological paralysis has been induced in adult CBA mice by intrapertioneal injections of small quantities of bovine γ globulin (BGG). The minimum paralyzing dose of BGG has been found to be between 50 and 200 μg. A dose as small as 2 μg, has been found to have a slight paralyzing effect. The time necessary for the induction of paralysis by 50 μg to 2 mg of BGG in CBA mice is 3-4 days. Paralysis is induced by only one component of BGG; this component is incapable of inducing an antibody response unless an injection of adjuvant is made at the same time or slightly before the injection of the antigen. The BGG is centrifuged at an RCF of 20,00-30,000 g to remove particulate matter. Failure to remove the particulate matter leads to sporadic immune responses in groups of mice injected with the protein. Mice given a paralyzing injection of BGG were subsequently challenged by an injection of BGG in Freund's adjuvant. The result of this challenge was tested by an injection of radioactively-labelled antigen and the elimination of this antigen from the circulation of the challenged mice was followed for several days. 'Immune elimination' can easily be distinguished from 'non-immune elimination'. The presence of antibody to the non-paralysing components of BGG in sera from paralysed mice was confirmed using the Ouchterlony gel-diffusion technique. [ABSTRACT FROM AUTHOR]

Fowls which tolerate foreign erythrocytes, but which have not received a transplant of variable cells, eventually lose tolerance when the supply of erythrocytes is discontinued. The loss follows, at an interval, after the foreign erythrocytes have been eliminated by the normal mechanism for removal of aged cells; earlier loss can be brought about by eliminating the foreign cells with passive antibody. The interval required for loss varies, for tolerance of homologous erythrocytes, from less than 5 to over 215 days. The age of the tolerance bird, and hence the duration of exposure to antigen, is the main factor influencing the interval required; the preceding level of tolerance exerts comparatively little effect. An attempt to terminate tolerance by adoptive immunization was only partially successful. [ABSTRACT FROM AUTHOR]

A state of immunological unresponsiveness to bovine serum albumin (BSA) or human gamma globulin (HGG) can be produced in guinea pigs by contact with these proteins either before and soon after birth, or even soon after birth alone. As judged by failure of treated animals to show immune elimination of the antigen, or anaphylaxis on reinjection, the animals were completely unresponsive when tested up to 5 months after birth. Administration of 6-mercaptopurine to guinea pigs, even in lethal doses, did not prevent the development of antibodies to HGG. After administration of BSA or HGG, labelled with 131I, to pregnant guinea pigs, their offspring at term contained significant amounts of the labelled proteins. HGG was catabolized in new-born guinea pigs with the same half-life as in adults. [ABSTRACT FROM AUTHOR]

Summary: Immune checkpoint inhibition with monoclonal antibodies is becoming increasingly commonplace in cancer medicine, having contributed to a widening of therapeutic options across oncological indications. Disruption of immune tolerance is the key mechanism of action of checkpoint inhibitors and although immune‐related adverse events are a typical class effect of these compounds, the relationship between toxicity and response is not fully understood. Awareness and vigilance are paramount in recognizing potentially life‐threatening toxicities and managing them in a timely manner. In this review article, we provide an overview of the clinical features, pathological findings and management principles of common immune‐related toxicities, attempting to provide mechanistic insight into an increasingly common complication of cancer therapy. [ABSTRACT FROM AUTHOR]

Oral tolerance refers to the specific inhibition of immune responsiveness to T-cell-dependent antigens contacted through the oral route before parenteral immunization. Oral tolerance to one protein does not inhibit immune responses to other unrelated proteins, but parenteral injection of tolerated antigens plus adjuvant into tolerant, but not normal, mice inhibits immune responses to antigens injected concomitantly or soon thereafter. The inhibitory effect triggered by parenteral injection of tolerated proteins is known as bystander suppression or indirect effects of oral tolerance. Intraperitoneal injection of ovalbumin (OVA) plus alum adjuvant in OVA-tolerant mice soon before skin injury inhibits inflammation and improves cutaneous wound healing. However, as OVA is not a regular component of mouse chow, we tested whether indirect effects could be triggered by zein, the main protein of corn that is regularly present in mouse chow. We show that intraperitoneal injection of a single dose (10 μg) of zein plus alum adjuvant soon before skin injury in mice reduces leucocyte infiltration but increase the number of T cells and the expression of resistin-like molecule- α (a marker of alternatively activated macrophages) in the wound bed, increases the expression of transforming growth factor- β3 in the newly formed epidermis and reduces cutaneous scar formation. These results suggest that indirect effects of oral tolerance triggered by parenteral injection of regular dietary components may be further explored as one alternative way to promote scarless wound healing. [ABSTRACT FROM AUTHOR]

Regulatory T (Treg) lymphocytes play a central role in the control of immune responses and so maintain immune tolerance and homeostasis. In mice, expression of the CD8 co-receptor and low levels of the co-stimulatory molecule CD28 characterizes a Treg cell population that exerts potent suppressive function in vitro and efficiently controls experimental immunopathology in vivo. It has remained unclear if CD8+ CD28low Treg cells develop in the thymus or represent a population of chronically activated conventional T cells differentiating into Treg cells in the periphery, as suggested by their CD28low phenotype. We demonstrate that functional CD8+ CD28low Treg cells are present in the thymus and that these cells develop locally and are not recirculating from the periphery. Differentiation of CD8+ CD28low Treg cells requires MHC class I expression on radioresistant but not on haematopoietic thymic stromal cells. In contrast to other Treg cells, CD8+ CD28low Treg cells develop simultaneously with CD8+ CD28high conventional T cells. We also identified a novel homologous naive CD8+ CD28low T-cell population with immunosuppressive properties in human blood and thymus. Combined, our data demonstrate that CD8+ CD28low cells can develop in the thymus of mice and suggest that the same is true in humans. [ABSTRACT FROM AUTHOR]

The 1960 Nobel Prize was awarded to Macfarlane Burnet and Peter Medawar for immunological tolerance. The Nobel Archives reveal that the two were never nominated together by anyone; Burnet had repeatedly been nominated for his virology studies, and the Medawar group (including Rupert Billingham and Leslie Brent) had been nominated independently for their transplantation work. A review of the 1950s literature suggests that tolerance had not yet, by 1960, reached the level of acceptance and acclaim in the immunological community to appear to justify the award. Burnet probably should have received the Prize for his virus work, and perhaps also for his Clonal Selection Theory, whereas Billingham and Brent should have shared in a Prize with Medawar for transplantation. If a Prize were to be given for tolerance, most agree that Ray Owen should have shared in it, for his work on cattle chimerism. It is suggested that the 1960 Nobel Prize to Burnet and Medawar for immunological tolerance may have been given for the wrong reasons and to the wrong associates. [ABSTRACT FROM AUTHOR]

Tumour progression is associated with immune-suppressive conditions that facilitate the escape of tumour cells from the regimen of immune cells, subsequently paralysing the host defence mechanisms. Induction of CD4+ CD25+ FoxP3+ T regulatory (Treg) cells has been implicated in the tumour immune escape mechanism, although the novel anti-cancer treatment strategies targeting Treg cells remain unknown. The focus of this study is to define the interaction between tumour and immune system, i.e. how immune tolerance starts and gradually leads to the induction of adaptive Treg cells in the tumour microenvironment. Our study identified hyperactivated mitogen-activated protein kinase kinase ( MEK)/extracellular signal-regulated kinase ( ERK) -signalling as a potential target for reversing Treg cell augmentation in breast cancer patients. In more mechanistic detail, pharmacological inhibitors of MEK/ ERK signalling inhibited transforming growth factor- β ( TGF- β) production in tumour cells that essentially blocked TGF- β- SMAD3/ SMAD4-mediated induction of CD25/interleukin-2 receptor α on CD4+ T-cell surface. As a result high-affinity binding of interleukin-2 on those cells was prohibited, causing lack of Janus kinase 1 ( JAK1)/ JAK3-mediated signal transducer and activator of transcription 3 ( STAT3)/ STAT5 activation required for FoxP3 expression. Finally, for a more radical approach towards a safe MEK inhibitor, we validate the potential of multi-kinase inhibitor curcumin, especially the nano-curcumin made out of pure curcumin with greater bioavailability; in repealing tumour-shed TGF- β-induced Treg cell augmentation. [ABSTRACT FROM AUTHOR]

CD4+ FOXP3+ regulatory T (Treg) cells constitute a heterogeneous and plastic T-cell lineage that plays a pivotal role in maintaining immune homeostasis and immune tolerance. However, the fate of human Treg cells after loss of FOXP3 expression and the epigenetic mechanisms contributing to such a phenotype switch remain to be fully elucidated. In the current study, we demonstrate that human CD4+ CD25high CD127low/- Treg cells convert to two subpopulations with distinctive FOXP3+ and FOXP3- phenotypes following in vitro culture with anti-CD3/CD28 and interleukin-2. Digital gene expression analysis showed that upon in vitro expansion, human Treg cells down-regulated Treg cell signature genes, such as FOXP3, CTLA4, ICOS, IKZF2 and LRRC32, but up-regulated a set of T helper lineage-associated genes, especially T helper type 2 (Th2)-associated, such as GATA3, GFI1 and IL13. Subsequent chromatin immunoprecipitation-sequencing of these subpopulations yielded genome-wide maps of their H3K4me3 and H3K27me3 profiles. Surprisingly, reprogramming of Treg cells was associated with differential histone modifications, as evidenced by decreased abundance of permissive H3K4me3 within the downregulated Treg cell signature genes, such as FOXP3, CTLA4 and LRRC32 loci, and increased abundance of H3K4me3 within the Th2-associated genes, such as IL4 and IL5; however, the H3K27me3 modification profile was not significantly different between the two subpopulations. In conclusion, this study revealed that loss of FOXP3 expression from human Treg cells during in vitro expansion can induce reprogramming to a T helper cell phenotype with a gene expression signature dominated by Th2 lineageassociated genes, and that this cell type conversion may be mediated by histone methylation events. [ABSTRACT FROM AUTHOR]

Summary The immune system is intricately regulated allowing potent effectors to expand and become rapidly mobilized after infection, while simultaneously silencing potentially detrimental responses that averts immune-mediated damage to host tissues. This relies in large part on the delicate interplay between immune suppressive regulatory CD4+ T (Treg) cells and immune effectors that without active suppression by Treg cells cause systemic and organ-specific autoimmunity. Although these beneficial roles have been classically described as counterbalanced by impaired host defence against infection, newfound protective roles for Treg cells against specific viral pathogens (e.g. herpes simplex virus 2, lymphocytic choriomeningitis virus, West Nile virus) have been uncovered using transgenic mice that allow in vivo Treg-cell ablation based on Foxp3 expression. In turn, Foxp3+ Treg cells also provide protection against some parasitic ( Plasmodium sp., Toxoplasma gondii) and fungal ( Candida albicans) pathogens. By contrast, for bacterial and mycobacterial infections (e.g. Listeria monocytogenes, Salmonella enterica, Mycobacterium tuberculosis), experimental manipulation of Foxp3+ cells continues to indicate detrimental roles for Treg cells in host defence. This variance is probably related to functional plasticity in Treg cell suppression that shifts discordantly following infection with different types of pathogens. Furthermore, the efficiency whereby Treg cells silence immune activation coupled with the plasticity in Foxp3+ cell activity suggest that overriding Treg-mediated suppression represents a prerequisite 'signal zero' that together with other stimulation signals [T-cell receptor (signal 1), co-stimulation (signal 2), inflammatory cytokines (signal 3)] are essential for T-cell activation in vivo. Herein, the importance of Foxp3+ Treg cells in host defence against infection, and the significance of infection-induced shifts in Treg-cell suppression are summarized. [ABSTRACT FROM AUTHOR]

Tolerance to donor transplantation antigens develops when recipients are made chimeric with donor bone marrow. To establish chimerism, the haemopoietic system of recipients typically is severely compromised. We report on a system in which chimerism develops without ablative therapies. Immunosuppression with cyclosporin A allowed the lower limb of a rat to be replaced by a microvascularized transplant from a fully allogeneic donor. Many donor-derived cells populated recipient lymph nodes and spleen, and most had the large size, irregular shape and strong major histocompatibility complex (MHC) class II expression that typify dendritic cells. Donor ceils were not found in the macrophage-rich regions of lymphoid tissues, but instead occupied splenic white pulp and lymph node cortex. The donor cells were derived from radiosensitive marrow precursors, as chimerism was abolished if the grafted limb was irradiated, or if muscle and skin flaps devoid of bone were grafted. Donor cells were rare or not detectable in blood, thymus and liver. Whereas lymphoid chimerism was prominent following limb transfer, donor cells were not detected 1–2 weeks after an injection of two femur equivalents of a marrow suspension. We suggest that dendritic cells that undergo rapid turnover in lymphoid organs are replaced from allogeneic precursors in bone grafts. The combination of cyclosporin and vascularized bone provides a means for inducing chimerism in lymphoid tissues of non-irradiated recipients. [ABSTRACT FROM AUTHOR]

Inducibility of immunological tolerance to a T-dependent antigen, human serum albumin, was studied in autoimmune mice (NZB, MRL/Mp-1pr/1pr and male BXSB mice), comparing with non-autoimmune mice (BALB/c, DBA/2, MRL/Mp- +/+ and female BXSB mice). Weekly injections of increasing doses of the tolerogen into DBA/2 mice induced T-cell tolerance without the participation of suppressor cells and without affecting B cells. All of the autoimmune mice tested were refractory to the tolerogen; partial tolerance (40%-60% responsiveness) was attained in mice aged 1 month, but not in older mice. By comparison, tolerance was induced in non-autoimmune mice to a similar degree irrespective of the age of the mice. The tolerance inducibility was also examined in reciprocal bone marrow cell (BMC) transfer experiments between NZB and DBA/2 mice and also BMC transfer into B10.D2 mice. It was shown that recipients of NZB BMC were more resistant to tolerance induction than those of DBA/2 BMC, while irradiated NZB mice receiving DBA/2 BMC were susceptible. Hence, it is suggested that the tolerance-resistant nature of the NZB mice was inherent in T-cell precursors in the bone marrow and not in the host environment. Similar findings in support of this notion were also observed in BSXB mice. The significance of tolerance resistance in the development of autoimmunity is discussed. [ABSTRACT FROM AUTHOR]

An increase was found in total macrophage numbers in the spleens of BALB/c mice bearing the plasmacytoma TEPC-183 compared with controls. The increase was shown to be confined to red pulp macrophages; white pulp macrophage numbers were normal as were the number of macrophages which took up hydroxyethyl starch. It is suggested that this increase in red pulp macrophages may account for the suppression of primary immune responses caused by spleen cells from TEPC-183 bearing mice. This effect may be due to increased numbers of normal macrophages rather than the generation of distinctive suppressor macrophages as suggested previously. [ABSTRACT FROM AUTHOR]

TN BSA injected at tolerogenic doses with a trace label of 14C showed an immediate fixation on serum proteins, red cells, lymphoid cells and. as far as could be determined, all organs in the body. The fixation on lymphoid cells was non-specific, at least initially. These results are discussed in relation to the mechanism of tolerance induction by TNBSA. [ABSTRACT FROM AUTHOR]

The article presents a study regarding the incubation of unprimed spleen B cells with high concentrations of hapten conjugates. The author explains that according to the results, tolerogenesis can occur in the absence of extracellular calcium. Calcium requirements for both antibody synthesis and B cell tolerance induction are investigated.

An immunofluorescent study has been made of IgG, IgM and IgA in the stomach of uninfected minimal disease pigs and pigs infected with a single dose of 100,000 third stage infective Hyostrongylus rubidus larvae, lmmunoglobulin-positive cells were present in both uninfected and infected animals. In infected animals both IgM and IgA immunocytes increased in numbers following infection and the numbers remained raised during the histotropic phase of worm development. No increase in IgG immunocyte numbers was noticed throughout the course of refection ( 100 days). [ABSTRACT FROM AUTHOR]

Discusses cellular mechanisms of the resistance to the induction of immunological tolerance. Differences in spleen PFC numbers between various strains of mice; Effect of aggregate-free HGG injection on spleen cells, thymus cells and bone marrow cells; Role of macrophages in resistance tolerance induction; Role of raised threshold of T cells for tolerance in causing the resistance to tolerance induction to aggregated HGG.

Lymph nodes-and to a lesser extent spleen cells-from guinea-pigs tolerant to DNCB contact sensitivity, when injected into normal syngeneic guinea-pigs, decrease the ability of the recipients to become sensitized to contact with DNCB. The difference between the complete tolerance transferred by parabiosis with tolerant partners and the partial tolerance induced by transfer of tolerant cells can be explained by the different numbers of cells homing in the recipients. The tolerogen does not play any role in the transfer of tolerance. [ABSTRACT FROM AUTHOR]

In an investigation of the ontogeny of lymphoid tissue in chick embryos to relate maturation of lymphocytes with immunological competence, the numbers and sizes of lymphocytes were determined in the thymus, bursa of Fabricius, spleen, femoral marrow and peripheral blood of embryos from the 12th to 21st day of incubation, and in 6-day-old chicks. Results showed the thyrnus to be the first fully developed and most active lymphocytopoietic organ, followed by the bursa. The bone marrow was not lymphocytopoietic; the spleen and bone marrow were mainly granulocytopoietic and erythropoietic; some morphological differences between thymic and bursal lymphocytes were shown by light microscopy. It appears that in embryos and young chicks the lymphocytes are derived from the thymus and bursa, but not the bone marrow. In tests of immunological competency, cells of the thymus, bursa, spleen, bone marrow and peripheral blood from. 12-21-day-old embryos and 6-day-old chicks were transferred to chorioallantoic membranes of 12-day-old recipient embryos. There were distinct differences between the ability of various lymphoid tissues to induce formation of chorioallantoic pocks or splenic enlargement. The thymus, spleen and peripheral blood elicited both lymphocytic pocks and splenomegaly, the bursa elicited splenomegaly only, and the bone marrow was ineffective. The bone marrow, however, induced formation of nonlymphocytic pocks. It is coneluded that the immunological activity of the chicken embryo is primarily effected by the thymus and bursa and that cell-mediated immunity appears in the 2nd week of incubation. [ABSTRACT FROM AUTHOR]

Adult normal mice and those mice which had been thymectomized, X-irradiated, and reconstituted either with bone marrow cells and thymus cells (TxXBT) or with bone marrow cells alone (TxXB), were given varying amounts (0.1-5 mg) of deaggregated soluble bovine serum albumin (sBSA). They were challenged 10 days later with an immunogenic form of BSA. TxXB mice were supplemented with normal thymus cells 3 days before the challenge. With any dose of sBSA, TxXBT and normal mice were made tolerant. Only 5 mg of sBSA, the highest dose in these experiments, was effective in inducing the tolerance in TxXB mice. The simultaneous administration of 5 mg of sBSA and 0.1 mg of alumprecipitated BSA plus 0.01 mg of endotoxin resulted in the priming in TxXBT mice but induced tolerance in TxXB mice. These results indicate that: (a) B-cell tolerance could be induced independently of the influence of T cells; (b) the tolerogen susceptibility of B cells may be lower than that oft cells; (c) such a weakly immunogenic agent as the mixture of tolerogen and immunogen could either activate the antibody response in the presence oft cells or induce B-cell tolerance in the absence of T cells. [ABSTRACT FROM AUTHOR]

Rabbits heterozygous as the 'b' locus (b4b6 or b5b6) were suppressed for b6 production. These suppressed rabbits were immunized to produce anti-allotypic antibody against: (a) determinants not possessed in their genotype; (b) the suppressed b6 determinants. [ABSTRACT FROM AUTHOR]

Homogenates of suspensions of the trypmostigote and amastigote forms of the Ernestina strain of Trypanosoma cruzi, derived from tissue cultures yielded two subcellular fractions which elicited strong delayed hypersensitivity reactions in rabbits. The 100,000 g x 90 minute fraction of T. cruzi homogenates gave rise to marked cell-mediated immunity. The 30,000 g x 35 minute fraction of these homogenates was also capable of eliciting a marked cell-mediated immune response. Cell-mediated immunity was assayed by experiments which established passive transfer, inhibition of blood mononuclear cell migration and blast transformation by T. cruzi-sensitized lymphocyte. Sensitized lymphocytes did not have observable effects on trypomastigotes of T. cruzi. The results of the experiments described here strongly suggest that constituents of intracytoplasmic particles of trypomastigotes and amastigotes of T. cruzi are involved in eliciting cell-mediated immunity in rabbits. [ABSTRACT FROM AUTHOR]

The repeated administration of bovine serum albumin by stomach tube to Charles River and Black Norwegian rats resulted in a state of partial tolerance to the antigen. A very small amount of antibody was detected in the serum at the end of the oral regime but anti-BSA-producing cells could not be demonstrated in the lamina propria, in the Peyer's patches of the small intestine, in the mesenteric nodes or in the spleen of these animals. Antibody was not demonstrated in the small intestinal contents or in the faeces of the same animals. The antigen was absorbed in the native form and not as constituent peptides bearing antigenic determinants in common with the native protein. Preliminary data, using a radioimmunoassay, indicate that the serum concentration of BSA after the administration of 25 mg of the protein by stomach tube, is in the range 1-10 ng/ml of serum. Preliminary experiments indicate that the state of partial tolerance could not be abrogated by syngeneic spleen cells or peritoneal exudate cells from normal rats. This form of tolerance therefore has some features in common with the state of tolerance induced by the parenteral administration of small amounts of bovine albumin (low zone tolerance). [ABSTRACT FROM AUTHOR]

HgA-positive red cells were treated in vitro with approximately 10 μmoles N-ethylmaleimide (NEM) per ml cells for 1 hour at 37° and then injected into the circulation of HgA-negative rabbits; all the cells were cleared within 24 hours After 1-3 months the animals were given a series of injections of untreated HgA-positive red cells at 3-monthly intervals. Five out of seventeen rabbits showed progressively diminishing survival of HgA-positive red cells with the development of anti-HgA. On the other hand, in eight rabbits red cell survival following three consecutive injections of untreated red cells was normal or almost normal and in four further rabbits survival was initially subnormal but became progressively longer and was almost normal following a third injection of cells. Thus, in as many as twelve out of seventeen animals (70 per cent) the survival of HgA-positive red cells following a third injection of untreated cells was normal or almost normal whereas this pattern was previously observed in only seven out of fifty-one animals (14 per cent) not given an initial injection of NEM-treated cells. It is concluded that the injection of NEM-treated HgA-positive red cells to HgA-negative rabbits induces a degree of immunological tolerance to the HgA antigen. [ABSTRACT FROM AUTHOR]

The capacity of CBA mouse B lymphocytes to bind polyvalent rabbit anti-mouse immunoglobulin antibody, even when this reagent is present in low concentration, was used as an index of a lymphocyte's B cell status. Various mouse tissues were held for 30 minutes at 0° with 0·2 μg/ml of 125I-labelled anti-Ig, and smear preparations of washed cells were examined, following radioautography, for their content of B cells. The survey covered two areas of B cell differentiation, namely the spontaneous emergence of B cells in the mouse foetus, and the development of B cells in lethally irradiated mice that had received early foetal liver as a source of haematogenous stem cells. The foetal survey suggested a multifocal origin of B cells, commencing 3 days before birth, in all major sites of erythromyelopoiesis, namely liver, spleen and bone marrow. Lymph nodes showed B cells later than did these organs, and thymus contained virtually no B cells at any stage. A rapid influx of B cells into lymph nodes took place shortly after birth. The CBA mouse is born with somewhat over 105 B lymphocytes in toto, of which the majority are in liver, spleen and blood. The irradiation-recovery study showed: (1) that B cells are, statistically, more sensitive to high dose irradiation than T cells; (2) that a B cell-free stem cell source can repopulate the B cell pool; (3) that repopulation is surprisingly slow; and (4) that numerical and functional recovery of B cells parallel each other to a reasonable degree. The significance of the results is discussed from the viewpoints of lymphocyte differentiation and immunological tolerance. [ABSTRACT FROM AUTHOR]

Immunological tolerance to synthetic polypeptides containing poly-L-proline has been induced in guinea-pigs by appropriate injections. The recovery from tolerance without further immunization has been followed by repeated skin testing. The tolerance involved both humoral antibody production and the development of delayed hypersensitivity. The results were interpreted on the basis of two hypotheses. (1) The avidity, between antigen and antibody is a function of both the accuracy of fit and the extent over which the fitting takes place. (2) Antibody produced in animals showing partial tolerance differs from anti- body in non-tolerant animals by a less perfect fit. Evidence is also presented that immunization with antigen in the presence of antibody to some only of its determinants favours an immune response to the remaining determinants. [ABSTRACT FROM AUTHOR]

Adult Wistar rats were injected with flagellin from Salmonella adelaide three times weekly for different periods of time. With the range of doses 100 fg to 100 μg (fg, femtograms), varying levels of immune responsiveness were demonstrable following challenge, but not one of the doses induced complete immunological tolerance, although a reduced antibody response was elicited in rats which received injections of 100 μg of flagellin. In contrast to this finding, complete tolerance could be demonstrated following challenge if rats, previously drained of lymph and lymphocytes from the thoracic duct for 5 days, were injected with either 100 μg of flagellin three times weekly or with 1 μg/g body weight/day for 6 weeks. Similarly, anti-lymphocyte serum treatment prior to the injection of antigen resulted in partial tolerance in adult rats and nearly complete tolerance in adult C57BL/Brad mice. The primary response to flagellin of C57BL mice was abrogated if ALS was administered prior to but not after the injection of antigen. The implications of these findings are discussed. [ABSTRACT FROM AUTHOR]

Flagellin (molecular weight 40,000) from Salmonella adelaide was reacted with CNBr to give mainly four peptide fragments, A, B, C and D, the largest of which (fragment A, molecular weight 18,000) retained all the serological activity of flagellin itself. Mixtures of the fragments or individual fragments were injected into neonatal or adult rats, either as a single dose in saline or in adjuvant, or in multiple doses in saline. Antibody titres, measured by bacterial immobilization, were compared with those given after an injection of flagellin. Fragment A and the complete CNBr digest of flagellin (the ‘digest’) were both immunologically active whereas fragments B, C and D were inactive. When given as a single injection in saline into adult rats, the ‘digest’ or fragment A was much less efficient than flagellin at inducing either a primary antibody response or the production of primed cells for a secondary antibody response. In contrast, the ‘digest’ or fragment A was effective at triggering primed cells to give a secondary antibody response. These findings were consistent with an interpretation given in detail elsewhere relating to ‘in vivo’ localization of labelled flagellin and fragment A in rat lymph nodes to the immune response. Fragment A and flagellin were equally immunogenic when injected in Freund's complete adjuvant. Rats given a course of injection of the ‘digest’ starting on the day of birth he- came almost completely tolerant to either flagellin or polymerized flagellin. Daily injections of the ‘digest’ or fragment A for 4 weeks or longer into adult rats resulted in a significant degree of tolerance to flagellin and to polymerized flagellin. Adult rats made tolerant in this way responded normally to BSA injected in Freund's complete adjuvant and to a slightly decreased extent to sheep RBC. It was concluded that by a process of partial degradation, a highly immunogenic substance, polymerized flagellin, had been converted into a preparation with strong tolerance-inducing properties. The relevance of this approach to trans- plantation antigens was discussed. [ABSTRACT FROM AUTHOR]

The generation in vitro of cells synthesizing haemolytic antibody to sheep erythrocytes (plaque forming cells—PFC) was shown to be due to the combined activity of two distinct populations of cells—macrophages and lymphocytes. Suspensions of cells from mice rendered tolerant to sheep erythrocytes by injection of a large dose of antigen and cyclophosphamide showed a greatly reduced capacity to generate PFC if tested within the first 17 days after treatment. This loss of capacity to mount an immune response in vitro was restored by suspensions of lymphocytes from spleens of normal mice. The lymphocytes from recently paralysed mice failed to generate PFC when incubated with preparations of normal macrophages. The macrophages from paralysed mice were as active as normal macrophages in generating PFC. Tolerance in this model is, therefore, associated with a loss of function in vitro of the lymphocytes in the spleens of such animals. Most spleens tested 3 weeks after induction of paralysis, when recovery in the intact animal is incomplete, had a normal capacity to generate PFC in vitro. [ABSTRACT FROM AUTHOR]

The particulate antigen, polymerized fiagellin, was shown to be effective both in immunological priming and in inducing tolerance in newborn Wistar rats. The following results were obtained: (1) A single injection of 100 ng or more at birth caused priming without a primary responses A secondary response could be elicited 7 or more days after birth with a dose of 10–100 μg. (2) Daily injections of 100 ng to 1 μg/g body weight of polymerized flagellin during the first 2 weeks of life abrogated the priming effect and in fact gave rise to a state of high dosage-zone immunological tolerance. (3) The injection of 1 μg to 10-5 μg/g body weight/day into newborn rats for 2 weeks gave rise to two zones of tolerance separated by a slight ’immunity hump’, which suggested the presence of some primed cells but fewer virgin cells following these intermediate doses. (4) The low zone of tolerance was induced by a dose of 10-4 pg/g body weight/ day, which was equivalent to an initial antigen concentration in the animal of about 10-20 M, if one adopts the simplified assumption that polymerized flagellin has a molecular weight of 10×106, High zone tolerance was induced by doses of 100 ng/g body weight/day or more and the immunity region by 1 ng/body weight/ day. (5) In the low zone, polymerized fiagellin appears to induce tolerance even better in newborn rats than the lower molecular-weight monomeric fiagellin. The extremely small amounts which are effective are difficult to explain, but raise the possibility of some antigen concentrating mechanism.

Immune and non-immune mesenteric lymph node and Peyer's patch cells were labelled in vitro with 51Crk and injected intravenously into infected and non-infected syngeneic guinea-pigs (Heston strain). From the distribution of the radioactive label in the small intestine (the site of infection of T. colubriformis) it was concluded that immune lymphocytes: (1) preferentially localize or 'home in' on the infection, (2) come into intimate contact with the parasite in the epithelium, and (3) rapidly undergo 'allergic death' or lysis at the site of infection. [ABSTRACT FROM AUTHOR]

Summary. Neonatal mice of the inbred strains NZB, Balb/c and C57B1 were injected with sheep, pig or chicken red cells at various ages and antibody plaque- forming cell (PFC) responses in their spleens measured. Marked strain differences were found, notably a high early response by NZB mice to sheep cells. Hybrid and backcross experiments suggested that this was genetically controlled by at least three genes. C57B1 mice were late in developing a response to all of the antigens tested. The kinetics of the PFC responses were interpreted as favouring an explanation not involving cell division in response to antigen. Thymectomy at birth reduced the PFC responses in 1-month-old mice of all three strains to the same low level, while thymectomy after 7 days left the PFC responses intact. It is argued that the thymus must be present for strain-specific immune responses to develop. [ABSTRACT FROM AUTHOR]

Minute amounts of Salmonella adelaide flagellin were shown to be capable of inducing tolerance in newborn Wistar rats. With the range of doses, 10-9−10-1 μg, the following results were obtained: (1) Tolerance could be induced in two zones of dosage by daily injections of flagellin during the first 2 weeks of life. The low zone corresponded to a dose of 10-7 μg/g body weight and the high zone to 10-3 μg/g body weight. Doses between these evoked an immune response. (2) Daily injections of flagellin for 6 weeks resulted in a shift in the dosage required for low zone tolerance from 10-7 μg/g body weight to 10-5 μg/g body weight. (3) The events of low zone tolerance occurred at an antigen concentration, which, in an organ such as the spleen of a newborn rat, never exceeded about 10-14 M. The high zone of tolerance corresponded to an antigen concentration of about 10-10 M.

Guinea-pigs injected with antigen in Freund's complete adjuvant develop delayed hypersensitivity to the antigen. This is reduced by the prior injection of the same antigen precipitated with alum. This may be termed immune deviation and has been shown to differ from immune tolerance. Four possible mechanisms for this phenomenon were considered: (a) that there was a specific defect in the cell population responsible for the passive transfer of delayed hypersensitivity; (b) that there was an antibody blocking the detection of delayed hypersensitivity; (c) that there was an antibody blocking the induction of delayed hypersensitivity; and (d) that the cells responsible for delayed hypersensitivity were desensitized in vivo. Experiments on the passive transfer of delayed hypersensitivity from deviated and control guinea-pigs showed that there was a defect in the cell population involved in the passive transfer of delayed hypersensitivity. Serum transfer failed to reveal evidence of antibody blocking the induction or detection of delayed hypersensitivity. Transfer of cells into recipients which had been pretreated with alum-precipitated antigen gave no evidence of desensitization in the PPD system. The findings with bovine γ-globulin were equivocal. It was concluded that there was a defect in the cell population involved in the passive transfer of delayed hypersensitivity and, in the absence of evidence for other mechanisms, this was attributed to a direct effect of the first injection of antigen on the cells responsible for the state of delayed hypersensitivity after the injection of the same antigen in Freund's complete adjuvant. [ABSTRACT FROM AUTHOR]

Measurement of the rate of elimination of 51Cr-labelled erythrocytes provides a reliable test of immunity in fowls. Chickens can be rendered tolerant of homologous and turkey erythrocytes, as judging by this test, by receiving a series of transfusions of irradiated blood. The series were arranged so that foreign cells remained present in the circulation from the time of hatching. Tolerance induced by this treatment is generally incomplete, but can last indefinitely. In some chickens the manifestation of tolerance of turkey erythrocytes is delayed, probably because of passive transmission of antibody from the damn. Chickens old enough to react against small transfusions of homologous blood can still be rendered tolerant by massive transfusions. Tolerance of the erythrocytes from an individual donor extends only slightly to those from other donors. Tolerance acquired in this way, through transfusion of irradiated blood, stands in contrast to the more stable and complete tolerance that can be acquired through administration of variable cells. Viable cells, on the other hand, provide a less sensitive test, for birds which tolerate skin homografts often eliminate rapidly erythrocytes from the same donor. [ABSTRACT FROM AUTHOR]

A new histocompatibility locus, H-4, in the first linkage group of the mouse, has been identified. The gene-order in this linkage group is H-1, c, p, with H-4 very close to p but its position relative to p undetermined. There is 8.5 ± 2.1 per cent crossing over between H-1 and c in the heterozygous female, 5.4 ± 3.7 per cent in the heterozygous male. At least 4 alleles at the H-1 locus have been identified. The distribution of H-1 alleles in various inbred and co-isogenic resistant stocks is shown in Table 11. The mean survival of skin grafts made between various co-isogenic strain pairs, differing at H-1, ranges from 32 to 91 days, with a minimum survival of individual grafts of 20 days and a maximum of 124 days. Ovarian grafts between the same strain pairs show much longer survival. The significance of these results for estimates of gene numbers is discussed; the higher published estimates are favoured. [ABSTRACT FROM AUTHOR]

Guinea pigs were rendered incapable of making circulating antibody against bovine serum albumin (BSA) or human gamma globulin (HGG), by prenatal and/or neonatal contact with these antigens. They were then treated with a water in oil emulsion of picryl BSA, or with HGG in Freund's adjuvant, or with HGG precipitated with excess rabbit antibody and suspended in a water in oil emulsion, such as to produce a state of delayed hypersensitivity to BSA or HGG respectively in control animals. The guinea pigs which would not make antibody failed to become hypersensitive to these antigens. In one group of unresponsive animals treatment with HGG in Freund's adjuvant resulted in antibody production, but no phase of delayed hypersensitivity was observed. [ABSTRACT FROM AUTHOR]

A state of acquired immunological tolerance to bovine gamma globulin (BGG) has been observed in CBA mice injected with 10 mg. BGG within 12 hours of birth. Tolerance was demonstrated by a lack of immune elimination of 131I labelled BGG (BGG-131I) after prior challenge with Freund's adjuvant containing BGG. The degree of tolerance was found to diminish when the time between the tolerance injection and the challenge injection with adjuvant was increased. Mice were found to be tolerant 4 months after injection of 10 mg. BGG at birth but other similarly treated mice were found to be partially immune when challenged 6 months after the tolerance injection. This diminution of tolerance could be prevented by injections of antigen into adult mice whilst they were still tolerant. Precipitin and haemagglutination tests showed that antibody to BGG was present in mice shown to be tolerant to BGG by the antigen-elimination technique. The Ouchterlony double-diffusion technique showed that the mice were tolerant to one fraction of BGG but immune to at least one other fraction. The tolerated fraction of BGG was identified by means' of starch-gel electrophoresis. [ABSTRACT FROM AUTHOR]

The natural response of immunocompetent adult animals to antigen inhalation is the development of T-lymphocyte mediated tolerance, particularly in the IgE-antibody class (Holt & Sedgwick, 1987). It has been suggested that this process functions as a protective mechanism to limit sensitization to aero-allergens. In the present report, it is shown that the inhalation tolerance process does not function during the early postnatal period, and the lack of this protective mechanism may contribute to the increased risk of allergic sensitization during infancy. These experiments also demonstrate that adoptive transfer of adult splenocytes to newborns confers adult capacity for tolerance development, which suggests that delayed maturation of certain T-cell subset(s) may underly this transfer defect. [ABSTRACT FROM AUTHOR]