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Although different models for rheumatoid arthritis have been studied, the pathogenesis in humans remains unknown. A possible mechanism is the crossreactivity between bacterial components and the target-tissue, the cartilage. The existence of this crossreactivity is supported by various data from clinical and experimental studies. Here we provide direct evidence that priming in vivo with cell wall fragments of Streptococcus pyogenes or Escherichia coli can induce a cellular and humoral anti-cartilage response in Balb/c mice in vitro. T cells isolated from these mice can be stimulated in vivo to proliferate by a variety of antigens among which arc the priming bacterium, an unrelated bacterium, small bacterial components and diverse antigens of cartilagenous origin. In bacterium-primed mice antibodies were also detected that displayed a reactivity to cartilage extract besides the reactivity to bacteria. A crossreactive response occurred in vivo in certain circumstances; a delayed type hypersensitivity reaction could be elicited in cell-wall-primed mice by challenge with cartilage extract. For the expression of this crossreactive response in vivo however, it was obligatory to attenuate the mouse's suppressor-circuit. In this paper we would suggest a mechanism for the pathology of chronic arthritis, based on repeated challenges with different bacterial stimuli. [ABSTRACT FROM AUTHOR]

The responses of thymocytes to Coneanavalin A (Con A), and interleukin 1 (IL-1), interleukin 2 (IL-2) and phorbol myristate acetate (PMA) were investigated. The enzyme 20-a-hydroxysteroid dehydrogenase (20αSDH) was used as a marker to distinguish between various populations of activated thymocytes. Thymocytes that were selected in Con A + pure or crude IL-2 expressed high 20αSDH activity, while those that were selected in Con A + recombinant IL-1 (rIL-1) or crude IL-1, or Con A + PMA expressed low 20αSDH activity. Both groups proliferate in response to Con A and had IL-2 receptors. After selection, the enzymatic phenotype was stable even if the cells were transferred from Con A + IL-2 to Con A + PMA (or IL-1) or vice versa. A third group was selected from thymocytes that were cultured in PMA + T cell growth factor (TCGF). This group expressed low levels of 20αSDH, had IL-2 receptors, but did not respond to Con A. This paper demonstrates that 20αSDH can be used as an enzymatic marker to distinguish between subpopulations of activated T cells, which have not been previously detected by the conventional surface markers. [ABSTRACT FROM AUTHOR]

This paper describes the course of infection and certain pathological changes in thymus-deprived and normal CBA mice after oral infection with Trichinella spiralis. Greater morbidity was found among deprived mice and deaths due to trichiniasis occurred solely in this group. The local inflammatory response in the gut and skeletal muscles was defective in deprived animals: compared to normal mice it was slower to develop, contained fewer cells and was inadequately sustained. There was a striking paucity of tissue eosinophils and this was correlated with failure of deprived mice to develop a blood eosinophilia. The parasites appeared to persist longer in the gut of deprived animals and progressively more parasites were recovered from the carcasses of these mice at later stages of the infection. The present findings indicate that thymus-dependent cell populations are implicated in the host response to T. spiralis; and some possible modes of action of T cells are discussed. [ABSTRACT FROM AUTHOR]

OTHER ARTICLES PUBLISHED IN THIS MINI-REVIEW SERIES ON Th17 CELLS Function and regulation of human T helper 17 cells in health and disease. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04037.x Induction of interleukin-17 production by regulatory T cells. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04038.x Are T helper 17 cells really pathogenic in autoimmunity? Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04039.x CD4+ T helper cells: functional plasticity and differential sensitivity to regulatory T cell-mediated regulation. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04040.x There has been a considerable amount of interest in the immunological community about new phenotypic subsets of CD4+ T cells, particularly cells that produce the cytokine interleukin (IL)-17 [named T helper type 17 (Th17) cells]. While the initial discovery of Th17 cells and the pathways that controlled their development was in the mouse, recent attention has shifted to the existence of these cells and the relevant upstream cytokine signals in humans. While it is clear that CD4+ T cells producing IL-17 exist in vivo, their relevance to disease pathogenesis is only just being understood. In this paper, we review the data regarding the generation of human Th17 cells in vitro and the evidence that this effector population is important in human disease states. [ABSTRACT FROM AUTHOR]

Because of the high variability of seasonal influenza viruses and the eminent threat of influenza viruses with pandemic potential, there is great interest in the development of vaccines that induce broadly protective immunity. Most probably, broadly protective influenza vaccines are based on conserved proteins, such as nucleoprotein (NP). NP is a vaccine target of interest as it has been shown to induce cross-reactive antibody and T cell responses. Here we tested and compared various NP-based vaccine preparations for their capacity to induce humoral and cellular immune responses to influenza virus NP. The immunogenicity of protein-based vaccine preparations with Matrix-M™ adjuvant as well as recombinant viral vaccine vector modified Vaccinia virus Ankara (MVA) expressing the influenza virus NP gene, with or without modifications that aim at optimization of CD8+ T cell responses, was addressed in BALB/c mice. Addition of Matrix-M™ adjuvant to NP wild-type protein-based vaccines significantly improved T cell responses. Furthermore, recombinant MVA expressing the influenza virus NP induced strong antibody and CD8+ T cell responses, which could not be improved further by modifications of NP to increase antigen processing and presentation. [ABSTRACT FROM AUTHOR]

In BALB/c adult mice, respiratory syncytial virus (RSV) infection enhances the degree of lung inflammation before and/or after ovalbumin (OVA) respiratory sensitization. However, it is unclear whether RSV infection in newborn mice has an effect on the immune response to OVA respiratory sensitization in adult mice. The aim of this study was to determine if RSV neonatal infection alters T CD4+ population and lung inflammation during OVA respiratory sensitization in adult mice. BALB/c mice were infected with RSV on the fourth day of life and challenged by OVA 4 weeks later. We found that in adult mice, RSV neonatal infection prior to OVA sensitization reduces the CD4+CD25+ and CD4+CD25+ forkhead protein 3 (FoxP3)+ cell populations in the lungs and bronchoalveolar lavage. Furthermore, it also attenuates the inflammatory infiltrate and cytokine/chemokine expression levels in the mouse airways. In conclusion, the magnitude of the immune response to a non-viral respiratory perturbation in adult mice is not enhanced by a neonatal RSV infection. [ABSTRACT FROM AUTHOR]

A.SW and B10.S mice share the same major histocompatibility complex (MHC) haplotype (H-2s). However, A.SW mice are susceptible to experimental autoimmune myocarditis (EAM) and develop severe disease after immunization with myosin, whereas B10.S mice are resistant. We found that naive A.SW mice have intrinsically increased total CD4+ T cell counts and increased proportions of CD4+ T cells in their spleens compared to B10.S mice. Among total CD4+ T cells, naive A.SW mice have a lower relative frequency of forkhead box protein 3 (FoxP3+)CD25+ regulatory T cells (Tregs). A.SW mice also had a higher proportion of CD4+ T cells and a lower proportion of Tregs in their hearts and spleen during EAM, with greater T cell activation and proliferation, compared to B10.S mice. These differences in the T cell compartment were not antigen-specific, as ovalbumin/complete Freund's adjuvant (OVA/CFA) or CFA immunization elicited the same differences in CD4+ T cells and Tregs between A.SW and B10.S mice. Moreover, A.SW mice had more T helper type 17 (Th17) cells and B10.S had more Th1 cells in their hearts. The higher percentage of CD4+ T cells and their enhanced potential to differentiate towards the Th17 pathway was also observed in naive A.SW mice. Interleukin (IL)-6 is required for Th17 induction. Interestingly, IL-6Rα expression was greater on naive A.SW CD4+ T cells, compared to B10.S CD4+ T cells, indicating that this intrinsic difference, together with a relatively lower Treg proportion of CD4+ T cells, might lead to heightened Th17 responses and greater susceptibility to autoimmunity in A.SW mice. [ABSTRACT FROM AUTHOR]

The mechanism underlying late-phase allergic reactions (LPR) remains incompletely understood. This study aimed to investigate the role of a newly described subset of T cells, interleukin (IL)-9 IL-10 T cells, in the pathogenesis of LPR. Using a T helper type 2 (Th2) inflammatory mouse model, we examined the frequency of IL-9 IL-10 T cells in the jejunum by immunohistochemistry. The LPR in the jejunum was observed afterwards. The cytokine profile of IL-9 IL-10 T cells was characterized and the major cytokine that plays the critical role in the initiation of LPR was investigated. Abundant IL-9 IL-10 T cells as well as inflammatory cell extravasation in the jejunal sections were observed in sensitized mice 48 h after specific antigen challenge. IL-9 IL-10 T cells expressed high levels of macrophage inflammatory protein 1 (MIP1) that could be enhanced by T cell receptor activation. MIP1 facilitated macrophage extravasation in local tissue. Macrophage-derived MIP2 contributed to neutrophil infiltration in the intestine in LPR. Pretreatment with anti-MIP antibody inhibited the LPR in the intestine. IL-9 IL-10 T cells play an important role in LPR. This subset of T cells has the potential to be a novel therapeutic target in the treatment of LPR and LPR-related inflammation. [ABSTRACT FROM AUTHOR]

SUMMARY The scurfy mutant mouse is the genetic and phenotypic equivalent of the single-gene human autoimmune disease immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX). The scurfy mutation disrupts the Foxp3 gene, a putative master switch for T regulatory cell development. Bone marrow transplant without conditioning was previously reported to be ineffective in scurfy mice, yet clinical remission occurs in transplanted human IPEX patients despite limited donor engraftment. In view of this contradiction, we sought to validate scurfy as a model for studying the pathogenesis and treatment of human IPEX, in particular the phenomenon of dominant immune regulation. One half of scurfy mice given bone marrow transplants after sublethal irradiation recovered and survived long-term with donor chimerism ranging from 1·7% to 50%. Early transfer of 2 × 107 normal T cell-enriched splenocytes also prevented or limited disease and permitted long-term survival. Donor T cells in rescued mice made up 3–5% of lymphocytes and became highly enriched for CD25+ T cells over time. Transfer of 106 CD4+ CD25+ sorted T cells showed some beneficial effect, while CD4+ CD25- cells did not. Thus, both partial bone marrow transplant and T-enriched splenocyte transfer are effective treatments for scurfy. These results indicate that scurfy results from a lack of cells with dominant immune regulatory capacity, possibly T regulatory cells. The potency of small numbers of normal cells indicates that IPEX may be a feasible target for gene therapy. [ABSTRACT FROM AUTHOR]

Naturally susceptible mice (C57BL/6) infected with M. avium (strain Weybridge) developed a population of splenic T cells which, on transfer to syngeneic recipient mice, conferred significant protection against a subsequent challenge inoculum of M. avium. Similar T cells from naturally resistant mice (A/J) did not protect syngeneic recipient mice. Growth of M. avium in donor mice only occurred in the C57BL/6 strain. Replication of M. avium in donor mice was necessary for the development of protective T cells. High numbers of killed mycobacterium did not induce immune T cells. In addition. A/J mice inoculated with increasing numbers of viable M. avium (which still did not replicate) failed lo develop protective T lymphocytes. Further studies indicated that no protective T cells were present in the M. avium-infected A/J mouse, although evidence for non-specific immunity in these mice was obtained. In addition, BCG (which grows progressively in A/J mice) stimulated a population of splenic T cells which protected recipient mice from subsequent infection with M. tuberculosis. [ABSTRACT FROM AUTHOR]

When Meth-A fibrosarcoma-bearing BALB/c mice were injected subcutaneously with 10 µg of recombinant human interleukin 2 (rIL-2) once a day for 10 days, tumour growth inhibition was in the range of 22-31% of that of the control animals. Anti-tumour effector cells against Meth-A were detected in the spleen cells of the tumour-bearing BALB/c mice injected with rIL-2, using a modified Winn-type neutralization assay with the auxiliary injection of rIL-2. To induce the strongest anti-tumour activity in this assay system, the following were necessary: 1) the effector cells were derived from tumour-bearing BALB/c mice; 2) the donors of the effector cells were injected with rIL-2:3) the recipient mice in the Winn assay were auxiliarily injected with rIL-2 (a modified Winn assay). The anti-tumour effector activity detected in the modified Winn assay was inhibited by treatment with anti-CD8 or anti-asialo GM1 antibodies plus complement (C), but not completely. We supposed that at least two kinds of anti-Meth-A effector cells with different surface antigens, positive for CD8 and asiato GM1 antigens, were induced in the Meth-A-bearing BALB/c mice injected with rIL-2; these populations seemed to function independently and at least partly as anti-tumour effector cells in this tumour-host system. These spleen cells showed in vitro cytoloxicity against Meth-A cells, which are resistant to NK cells, if the activity was measured inn 24 h 51Cr-release assay in the presence of rIL-2. [ABSTRACT FROM AUTHOR]

Immunization of C57BI/6 mice with Torpedo acetylcholine receptor (AChR) leads to EAMG. experimental autoimmune myasthenia gravis, with characteristic clinical. electrophysiological. and immune features. Present in the lymphoid organs of mice with EAMG arc AChR specific suppressor T cells: these cells can be grown in vitro as T cell lines. These lines are able to suppress the in vitro response lo AChR. and can suppress the in; vivo development of EAMG. [ABSTRACT FROM AUTHOR]

C57BL/6 were infected intravenously with 107 Mycobacterium lepraemurium (MLM). At increasing time intervals after infection different isolated splenic cell subpopulations were tested for their ability to suppress the mixed lymphocyte reaction (MLR) of normal syngeneic mouse splenocytes. During the first 6 months after infection neither T depleted nor plastic adherent spleen cells from infected mice exerted a suppressive activity on the normal mouse allogeneic proliferative response. Conversely, splenic T cells from MLM infected mice exhibited suppressive activity as early as 2 months after infection. Attempts to characterize the Lyt phenotype of splenic suppressor T cells from 6 months infected mice showed that both Lyt 1 +2- and Lyt 2+ enriched cell subsets possessed the ability to suppress the MLR of the normal mouse spleen cells and Lyt 1 +2- T cells were shown to be more efficient suppressors than Lyt 2+ cells. [ABSTRACT FROM AUTHOR]

Reconstitution of Semliki forest virus infected nude mice with spleen cells from their immunocompetent nu/+ litter mates resulted in an abolition of the otherwise persistent brain virus, production of anti-SFV IgG, and development of normally absent brain pathology. The brain pathological changes, including demyelination, seem to be mediated by T cells, and are maximum 14 days after sensitization of the reconstituting spleen cells. Sensitization of the spleen cells 7 days before transfer to the nude mice results in pathological changes advanced by about 8 days, compared to reconstitution with unsensitized cells. The involvement of T cells in the virus-induced pathology is discussed. [ABSTRACT FROM AUTHOR]

Experimental autoimmune orchitis (EAO) developed in (C57B1/6Cr × A/JCr)F1 mice 3-4 months after neonatal thymectomy (Tx) without any sensitization. The age of Tx was critical for induction of EAO: Tx at day 3 (Tx-3) was effective, but Tx at day 0 or day 7 was not effective. This lesion resulted in atrophy of the testis and was characterized by disappearance of mature sperms, formation of multinuclear giant cells in seminiferous tubules and infiltration of lymphocytes in the stroma. Epididymitis was observed prior to the development of EAO. Presence of circulating autoantibody(s) against sperms (ASA) was demonstrated by indirect immunofluorescence. The acrosomal area of mature sperms, but not of immature spermatids, was stained strongly. The incidence of EAO and titre of ASA increased when Tx-3 mice were unilaterally vasectomized (Vx). The majority of mice with high titres of circulating ASA were sterile. Epididymitis and orchitis could be prevented in Tx-3 mice by injection of adult spleen cells on day 4. The most effective source was normal male. Spleen cells from normal female donors and day-0 orchidectomized (Orx) donors were less effective, while those of Tx-3 male and female donors failed to prevent epididymitis and orchitis. The cell population in normal male spleen effective in preventing epididymitis was shown to be a T cell population (Thy 1+, Ig-) by experiments with respective antisera treatment. These results showed that sensitization with sperm autoantigen occurred in the epdidymis after Tx-3, more efficiently after Tx-3 plus unilateral Vx, and that this autosensitization was prevented by a specific suppressor T cell population, which was present in normal males hut absent in Tx-3 mice. [ABSTRACT FROM AUTHOR]

Feeding of a protein antigen to adult mice results in reduced humoral and cell-mediated immune (CMI) responses when that antigen is subsequently presented, and also causes activation of suppressor cells in the gut-associated lymphoid tissues (GALT). We have attempted to abrogate this tolerance to fed antigen by pretreating mice with 100 mg/kg cyclophosphamide before oral immunization and challenge with ovalbumin. Cyclophosphamide-pretreated mice did not develop serum haemagglutinating antibodies, nor systemic CMI (as assessed by skin testing) after ovalbumin feeding. However, evidence that CMI had been induced in the GALT was provided by the significant inhibition of migration of mesenteric lymph node cells from cyclophosphamide-pretreated animals, but not from other control groups, in the presence of ovalbumin. Our previous work on CMI reactions in the small intestine has shown that the cell production rate in the crypts of Lieberkuhn and the intraepithelial lymphocyte count are reliable although indirect measures of mucosal CMI. Cyclophosphamide-pretreated, ovalbumin-immunized animals, which had been fed 0.1 mg ovalbumin daily for 10 days before killing, had increased crypt cell mitoses, and increased intraepithelial lymphocyte counts, indicating the presence of mucosal CMI response to ovalbumin. Mechanisms whereby cyclophosphamide pretreatment leads to abrogation of tolerance and induction of mucosal CMI are discussed. [ABSTRACT FROM AUTHOR]

In order to study T-cell function related to the production of autoimmune nephropathy, we immunized random-bred mice, homozygous athymic nude (nu/nu) mice and heterozygous hairy (nu/+) mice with human glomeruli contained in Freund's complete adjuvant. The random-bred and heterozygous hairy mice developed circulating antibodies to mouse and human kidney and an autoimmune glomerulotubular nephropathy, while the nude mice, even after prolonged immunization, developed neither antibodies nor nephropathy. We therefore concluded that the development of autoimmune glomerulotubular nephropathy in mice requires the presence of functioning T-cells. [ABSTRACT FROM AUTHOR]

An in vitro model for the study of T-cell ontogeny is presented. The generation of mitogen responsive thymocytes in embryonic mouse thymus using an organ culture system is described. The pattern of development of mitogen responsiveness in vitro is similar to that seen in vivo except that responses were greater and appeared later in culture than in thymus of a temporally equivalent age in vivo. This suggests that organ culture selectively enriches T-cell activity and thus offers a novel approach to the analysis of T-cell reactivity as well as to the understanding of defects in T-cell development. [ABSTRACT FROM AUTHOR]

An in vitro study of the spleen leucocyte migration ability and the phytohaemagglutinin (PHA) stimulated peripheral lymphocyte response was made on cells derived from mice treated by azathioprine, immune stimulation, or thymectomy and azathioprine. These responses were compared with those shown by normal mice and found to be considerably depressed. Thymectomy combined with azathioprine produced the greatest change which persisted at 40 days. These changes suggested that azathioprine in common with thymectomy, antilymphocyte globulin and radiotherapy produced some of its immunosuppression by depressing T-cell function. [ABSTRACT FROM AUTHOR]