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Omalizumab is an effective therapeutic humanized murine IgE antibody in many cases of primary systemic mast cell activation disease (MCAD). The present study should enable the clinician to recognize when treatment of MCAD with omalizumab is contraindicated because of the potential risk of severe serum sickness and to report our successful therapeutic strategy for such adverse event (AE). Our clinical observations, a review of the literature including the event reports in the FDA AE Reporting System, the European Medicines Agency Eudra-Vigilance databases (preferred search terms: omalizumab, Xolair®, and serum sickness) and information from the manufacturer’s Novartis database were used. Omalizumab therapy may be more likely to cause serum sickness than previously thought. In patients with regular adrenal function, serum sickness can occur after 3 to 10 days which resolves after the antigen and circulating immune complexes are cleared. If the symptoms do not resolve within a week, injection of 20 to 40 mg of prednisolone on two consecutive days could be given. However, in MCAD patients whose adrenal cortical function is completely suppressed by exogenous glucocorticoid therapy, there is a high risk that serum sickness will be masked by the MCAD and evolve in a severe form with pronounced damage of organs and tissues, potentially leading to death. Therefore, before the application of the first omalizumab dose, it is important to ensure that the function of the adrenal cortex is not significantly limited so that any occurring type III allergy can be self-limiting. Electronic supplementary material The online version of this article (10.1007/s00210-020-01886-2) contains supplementary material, which is available to authorized users.

The application of specific and proven guidelines is required for flow cytometric nuclear DNA analysis, which can provide precise information on genomic quantitative modifications and the proliferative activity of tumour tissues, clinically useful for prognosis and monitoring of therapy and recurrencies. The authors review the various protocol phases to be followed for a correct analysis and discuss the main problems that can be encountered in the procedural steps and in interpreting the histograms.

Lymphoepithelial complexes known as thymic "nurse" cells (TNC) have been isolated and described in the thymus of several animal species including man. Most of the investigations on TNC have been carried out in enzymatically digested thymuses in which TNC were isolated by differential sedimentation. In the present study we demonstrate TNC in immunohistochemically stained sections of human thymus as ring-shaped cells completely enclosing thymocytes and localized not only in the cortex, but also at the corticomedullary junction where they have not been previously described. TNC expressed epithelial markers [low and high molecular weight keratins identified by 35 beta H11 and 34 beta E12 monoclonal antibodies, a cortical antigen shared with neuroectodermal neoplasms recognized by the GE2 monoclonal antibody, and tissue polypeptide antigen (TPA:B1)], class II histocompatibility antigens (HLA-DR), and thymosin alpha 1. Double staining experiments with the nuclear proliferation-associated antigen Ki-67 and the cortical epithelium marker GE2 showed that most thymocytes enclosed in these cortical TNC were not proliferating. The antigens expressed by TNC indicate that not only cortical, but also medullary epithelial cells are part of the TNC system. The possible role of TNC in the education and maturation of thymocytes is discussed.

A cross-sectional survey was undertaken with the European Union (EU) Member States and Norway and Iceland to describe seasonal influenza immunisation in the 2006-7 season, in particular to identify country-specific recommendations for risk groups, obtain vaccine uptake information and allow comparison with global recommendations. A standardised questionnaire was completed electronically by each country's project gatekeeper. Of the 29 countries surveyed, 28 recommended seasonal influenza vaccination for older age groups (22 for those aged > 65 years), and in one country vaccine was recommended for all age groups. All countries recommended vaccinating patients with chronic pulmonary and cardiovascular diseases and most countries advised to immunise patients with haematologic or metabolic disorders (n=28), immunologic disorders (n=27) and renal disease (n=27), as well as residents of long-term care facilities (n=24). Most countries recommended vaccination for staff in hospitals (n=25), long-term care facilities (n=25) and outpatient clinics (n=23), and one-third had such recommendations for workers in essential (n=10), military (n=10) and veterinary services (n=10) and poultry industry (n=13). Eight countries recommended vaccine for pregnant women; and five advised to vaccinate children (with age limits ranging from 6 months to 5 years). Twenty countries measured influenza vaccine uptake among those aged > 65 years (range 1.8%-82.1%), seven reported uptake in healthcare workers (range 14%-48%) and seven assessed coverage in persons with underlying medical conditions (range 27.6%-75.2%). The data provided by this study can assist EU states to assess and compare their influenza vaccination programme performance with other countries. The information provides a comprehensive overview of policies and programmes and their outcomes and can be used to inform joint discussions on how the national policies in the EU might be standardised in the future to achieve optimal coverage. Annual surveys could be used to monitor changes in these national policies.

In May 2003, the 56th World Health Assembly (WHA) recommended influenza vaccination for all people at high risk defined as the elderly and persons with underlying diseases [1]. The WHA countries, including all European Union (EU) Member States, also committed to the goal of attaining vaccination coverage of the elderly population of at least 50% by 2006 and 75% by 2010 and to having mechanisms for monitoring the uptake [1]. To date there has been no published survey on how successful European countries have been in implementing this WHA resolution.

Polymorphonuclear granulocytes (PMN) are commonly considered short-lived cells playing an efficient role in primary host defense via phagocytosis and release of cytotoxic compounds and inflammatory cytokines. Purified PMN do not express HLA-DR and CD69 molecules on cell surface, but they can be induced to do so by co-culture with peripheral blood derived mono-lymphocytes. De novo cell-surface expression of HLA-DR was also induced in PMN by co-culture with cell lines of lymphoid phenotype, but not with cell lines of myeloid phenotype. CD69 expression was not induced by co-culture with any of the cell lines used in the present study. In addition, we have observed induction of HLA-DR surface expression on PMN by culture in presence of culture supernatant of one of the cell lines of lymphoid origin, RPMI-8866. Quantitative analysis of HLA-DR and CD69 expression in stimulated PMN allowed us to divide PMN donors in two main groups, one with low expression and the other with high expression of the two molecules. HLA-DR surface expression was not altered by treatment with CHX and BFA, and RT-PCR analysis of total RNA from resting and stimulated PMN with RPMI-8866 supernatant did not detect the presence of any specific HLA-DR and CIITA transcript. Flow-cytometry and fluorescence microscopy analysis of resting PMN revealed the presence of HLA-DR molecules localized in intracellular vesicular-tubular structures. These data show that a reservoir of HLA-DR molecules is stored in the cytoplasm of human resting PMN and can be released to reach cell surface by a mobilization mechanism induced by cell surface interactions with selected cell types and sometimes with molecules released in culture supernatants.

The growth dynamics of multicell tumour spheroids (MTS) were analysed by means of mathematical techniques derived from signal processing theory. Volume vs. time trajectories of individual spheroids were fitted with the Gompertz growth equation and the residuals (i.e. experimental volume determinations minus calculated values by fitting) were analysed by fast fourier transform and power spectrum. Residuals were not randomly distributed around calculated growth trajectories demonstrating that the Gompertz model partially approximates the growth kinetics of three-dimensional tumour cell aggregates. Power spectra decreased with increasing frequency following a 1/f(delta) power-law. Our findings suggest the existence of a source of 'internal' variability driving the time-evolution of MTS growth. Based on these observations, a new stochastic Gompertzian-like mathematical model was developed which allowed us to forecast the growth of MTS. In this model, white noise is additively superimposed to the trend described by the Gompertz growth equation and integrated to mimic the observed intrinsic variability of MTS growth. A correlation was found between the intensity of the added noise and the particular upper limit of volume size reached by each spheroid within two MTS populations obtained with two different cell lines. The dynamic forces generating the growth variability of three-dimensional tumour cell aggregates also determine the fate of spheroid growth with a strong predictive significance. These findings suggest a new approach to measure tumour growth potential.

Inside the thymus, thymic epithelial cells and thymocytes show an interdependent relationship for their functional differentiation and development. As regards possible interdependency for their mutual survival, it is clear that lympho-epithelial adhesion can control the survival of developing thymocytes whereas the effects of lymphoid adhesion on epithelial cell survival have never been described. To address this issue, we performed co-cultures between normal human thymic epithelial cells (TEC) and a mature lymphoid T cell line (H9) or unfractionated thymocytes. TEC were induced to apoptosis by growth factor deprivation and the level of cell death was measured by flow cytometry. TEC stimulated by cell adhesion showed a significant reduced apoptosis when compared to the control and this phenomenon was associated with increased binding activity of NF-(kappa)B, as measured by gel shift analysis. The activation of NF-(kappa)B was necessary to promote survival, since its inhibition by acetyl salicylic acid prevented the promoting effect. The mAb-mediated crosslinking of (alpha)(3)(beta)(1) was considered as a potential inducer of TEC survival, since we have previously demonstrated that the engagement of this integrin was able to induce NF-(kappa)B activation in TEC. The crosslinking of (alpha)(3)(beta)(1), which clustered at the lympho-epithelial contact sites, partially reproduced the promoting activity of cell adhesion. These results highlight that lympho-epithelial adhesion can control the survival of thymic epithelial cells through an intracellular pathway which requires the activation of NF-(kappa)B and is triggered by integrins of the (beta)(1) family.

CD23, the low affinity receptor for IgE, is a 45 kilodalton molecule belonging to the C-type lectin family, some members of which have been identified as adhesion molecules. Since it has been described upregulated in different cells in chronic inflammatory diseases and in rheumatoid arthritis in particular, where neutrophils are directly involved in tissue damage, our interest, in this work, has been focused on the expression and regulation of this antigen on neutrophil membrane. We studied 22 patients suffering from rheumatoid arthritis and 22 healthy control subjects. CD23 expression on neutrophil membrane was analyzed by immunofluorescence. Neutrophils of 9 out of 22 patients expressed CD23 molecules, neutrophils of 11 out of 22 patients expressed CD23 only after 24 h of incubation in RPMI; only 2 out of 22 patients did not express the CD23 antigen on neutrophil membrane either after isolation or after a 24 h incubation. On the contrary neutrophils isolated from healthy subjects did not express CD23 molecules upon isolation. Only in 7/22 control subjects neutrophils resulted positive after 24 h of incubation in RPMI. Moreover, we found that in our experimental conditions the presence of IFN-g or GM-CSF alone or in combination with IL-4 inhibited CD23 expression during the 24 h incubation. Our results show that there is a strong association between neutrophil ability to express CD23 and rheumatoid arthritis, and that such expression may be regulated by GM-CSF, IFN-gamma and IL-4.

Interleukin-6 (IL-6) is a multifunctional cytokine, which regulates the immune response by polyclonal B cell activation and differentiation; it enhances peripheral T lymphocyte responses, thymocyte growth and induction of cytotoxic T cell differentiation [1]. Many clinical and experimental observations suggest that IL-6 could be involved in pathogenetic processes; in fact, elevated levels of IL-6 have been detected during autoimmune diseases, infections, and tissue injury. It has been shown that cultured human thymic epithelial cells (TECs) are able to secrete IL-6 both constitutively and after stimulation with interleukin-1s (IL-1s) and/or LPS [2]. Some authors have suggested that TEC IL-6 production may be related to the thymic abnormalities found with a high frequency in Myasthenia Gravis (MG) [3]. Thymoma is found in about 10% of the MG patients, while hyperplastic thymus is often observed in MG female patients with young-age at onset. The thymus has estrogen receptors [4]; these steroids modulate IL-6 production in different tissues, such as bone marrow-derived stromal cells, osteoblasts and blood mononuclear cells in vitro [5, 6, 7] and are able to increase secretion of thymic hormones by TECs in vitro [8].

We have assayed the sensitivity of Jurkat cells in different growth phases to an anti-CD5-ricin A chain (ST.1-RTA) immunotoxins (IT). Jurkat cells proliferated exponentially until a stationary growth phase was reached. Proliferating and stationary cells displayed marked differences in sensitivity to ST.1-RTA treatment; the time required to kill one log of target cells (T10) was 70 h in proliferating and 12 h in stationary cells, respectively. Differences in sensitivity to IT treatment were greatly diminished by the addition of the IT enhancer monensin (T10 = 4.9 and 3.5 h in proliferating and stationary cells, respectively). Binding and internalization studies carried out with fluoresceinated ST.1 mAb revealed that the higher sensitivity of stationary cells to ST.1-RTA treatment was not due to an increased uptake or to faster internalization kinetics of IT molecules in this cell population; rather, our data indicated that a different intracellular routing of IT molecules took place in the two cell populations. Mathematical modeling of experimental data allowed us to calculate the efficiency of the intracellular transport of IT molecules toward a subcellular compartment facilitating toxin translocation to the cell cytosol. The IT intracellular processing in stationary cells was 5.5-fold more efficient than in proliferating cells. This value strictly correlated with the higher sensitivity of the stationary cell population to ST.1-RTA treatment.

The potentiation of monoclonal antibody/ligand toxin (immunotoxin) cytotoxicity by the ionophore monensin (Mo) or by human serum albumin-monensin (HSA-Mo) conjugates was investigated. Since disulfide cross-linked HSA-Mo (HSA-SPDP-Mo) is rapidly inactivated by human serum (M. Colombatti et al., Cancer Res., 50: 1385-1391, 1990), we synthesized thioether cross-linked HSA-Mo conjugates (HSA-SIA-Mo). HSA-SIA-Mo is resistant to treatment with reducing agents (e.g., glutathione, dithiothreitol) and shows potentiating activity identical to that of Mo or of HSA-SPDP-Mo, enhancing immunotoxin (IT) cytotoxicity 45-35,000-fold. Human leukemic and tumor cell lines are highly sensitive to treatment with IT in combination with Mo, HSA-SPDP-Mo, or HSA-SIA-Mo (concentration required to inhibit protein synthesis by 50%, 10(-10)-2.5 x 10(-13) M). IT potentiation by both types of HSA-Mo conjugates, however, is inhibited by whole human serum. In contrast, human cerebrospinal fluid has no effect on the potentiation of IT by Mo or HSA-Mo conjugates. The serum blocking factors reside mostly in a Mr 40,000-90,000 protein fraction. Serum components of low molecular weight (less than 10,000) show no detectable effect upon the stability of HSA-Mo conjugates. The toxicity of HSA-SIA-Mo in vivo was investigated by intrathecal injections in rats. Concentrations of up to 60 micrograms/kg can be injected into the brain with only transient neurological sequelae. We therefore conclude that if the systemic delivery of HSA-Mo conjugates for the potentiation of ricin A chain-IT presents some limitations due to the blocking effect of serum, the application of HSA-Mo conjugates in combination with ricin A chain-IT for regional tumor therapy in the brain appears more promising.

We have investigated the potentiation of transferrin [Tfn]-toxin [Tfn-ricin toxin A chain (RTA) and Tfn-So6 saporin toxin] and monoclonal antibody-RTA conjugates by monensin (Mo) and by a human serum albumin (HSA)-monensin conjugate in vitro. The in vivo survival and in vitro and in vivo toxicity of HSA-Mo were also studied; monensin was chemically linked to HSA carrier protein via a disulfide bridge. HSA-Mo was 2-13-fold less toxic than Mo for cells in vitro. HSA-Mo was active in the same concentration range as Mo in potentiating mAb-RTA and Tfn-toxin conjugates reactive with Tfn receptors expressed by different cell lines in monolayer cell cultures. Multicell tumor spheroid cultures were used to investigate the target cell killing effect of cytotoxic conjugates and HSA-Mo in three-dimensional structures mimicking the properties of nonvascularized micrometastases. Spheroids 300-400 microns were as sensitive to Tfn-RTA and HSA-Mo in combination as monolayer cells. After 24 h incubation at 37 degrees C in human serum about 2% HSA-Mo molecules remained available for immunotoxin potentiation and about 10% after 24 h incubation in human cerebrospinal fluid. BALB/c mice tolerated injections of 2 mg/kg HSA-Mo i.v. and of 16 mg/kg i.p. The HSA-Mo half-life in the serum of BALB/c mice was 0.5 h. Following i.v. injection about 0.5% of the initial HSA-Mo persisted in the circulation at 24 h.

To ascertain whether thymic lymphocytes represent suitable targets for HIV-1 infection, we infected thymic cell suspensions from normal donors with HIV-1 (HTLV-IIIB strain). We found that, in vitro, thymic lymphocytes are readily infected and highly permissive for HIV-1 replication. In addition, immature cells with the CD4+/CD8+ phenotype, most likely the precursors of mature circulating CD4+ and CD8+ lymphocytes, showed a marked susceptibility to viral infection and replication. These findings suggest that thymus infection may play a triggering role in the pathogenesis of AIDS, particularly in pediatric cases, and may partially explain the lack of restoration of peripheral CD4+ lymphocytes killed by HIV-1.

The role of diphtheria toxin (DT) B-chain subdomains in DT cytotoxicity and immunotoxin mechanism of action has been investigated. OKT3 (mAb to the CD3 surface Ag of human T lymphocytes) was conjugated to DT or the DT mutant CRM 1001, which has a cys----tyr substitution at position 471 of the B chain. OKT3-CRM 1001 immunotoxin was about 1400-fold less cytotoxic for CD3 Jurkat cells than OKT3-DT and had a 12-fold slower kinetics of protein synthesis inactivation, CRM 1001 killed DT-sensitive Vero cells at a 5000-fold higher concentration than DT. Its cell surface-binding activity was comparable to DT. Based on kinetics of cell inactivation, toxicity determination at low extracellular pH and Triton X-114 distribution, it was concluded that CRM 1001 is defective in at least one crucial step of toxin penetration and is unable to cross cell membranes as efficiently as DT. The substituted cysteine appears to be important for DT translocating functions. Data on the function of DT B-chain subdomains are relevant for the study of whole toxin conjugates and their mechanism of action.

The effect of various concentrations (0.015 - 10 micrograms/ml) of Levamisole (LMS) on the peripheral lymphocytes of patients with malignant lymphomas (ML) and normal donors was investigated in vitro. The parameters studied include: E rosettes forming cells (total T lymphocytes), active E rosettes (early T lymphocytes) and DNA synthesis induced by pitogens PHA and Con A. LMS improved significantly lymphocyte response both in patients with ML and normal donors when the cells were stimulated by Con A. In both groups no significant effect was observed on the response to PHA nor on the percentage of E-rosettes, whereas the mean number of active E rosettes was significantly increased on all concentrations of the drug. While in the normal subjects a positive statistical correlation between active E-rosettes and Con A response was observed, in patients with ML an inverse correlation was found. This latter correlation was partially reversed by LMS. These results indicate that LMS, both in normals and in patients with ML, interacts with a specific cell subset (early rosetting lymphocytes), with different functions in normal and pathological situations. The drug shows an effect on the immunological handicap of lymphocytes of patients with ML.

Physical cell separations are employed in a number of investigations in cell biology, immunology, haematology, etc., when the study of homogeneous cell populations is required. Differences in physical characters are reflected in the various functions and differentiation stages of the individual cell lines, which can be concentrated and separated into discrete cell classes by these methods. The correct utilization of the separation techniques mainly depends on the knowledge of the physical laws on which they are based. This paper discusses the theoretical background and a practical application of a combined separation procedure which uses velocity sedimentation and linear density gradient and also gives a double check of the physical data obtained in the different experiments. As an example of this analysis, cells from the lymph nodes of Hodgkin's patients were separated, and the physical parameters as well as some sources of 'error' in the experimental results obtained with these 'Hodgkin's cells' are reported and discussed.

Present experiments have been carried out to elucidate the role of some factors influencing the oncogenic effect of chemical carcinogens in newborn animals. Mice of Swiss, C3Hf/Gs, and C57BL strains were injected at birth, subcutaneously or in the thymus region, with either 20-methylcholanthrene (MC) or 9,10-dymethyl-1,2-benzanthracene (DMBA). The most frequent neoplastic lesions observed in the various experimental groups were: pulmonary adenomas, malignant lymphomas, subcutaneous sarcomas, and hepatomas. The incidence of different tumors varied according to the strain characteristics, route of administration and type of carcinogen. Susceptibility to lung carcinogenesis appeared to be highest for Swiss mice, intermediate for C3Hf/Gs and low for C57BL mice, receiving MC or DMBA, in accordance with the known data oh spontaneous incidence of these tumors in the same strains. DMBA was found more effective as leukemogenic agent than MC, when tested in Swiss and C57BL strains. The incidence of malignant lymphomas obtained by direct injection of either carcinogens in the thymic region was much larger than that observed in mice treated subcutaneously with even higher doses of chemicals. Sarcomas occurred exclusively at the site of injection and only in animals receiving carcinogens by subcutaenous route, MC being more effective than DMBA. As regard to development of hepatomas, high incidence of these tumors was observed only in male mice of C3Hf/Gs strain treated with DMBA. On the basis of present results and of those obtained with other chemical agents, the possible mechanisms underlying the higher susceptibility of newborn versus adult animals to chemical as well as viral carcinogenesis are briefly discussed.

Bone marrow megakaryocytes from mice injected with Graffi or Passage A Gross viruses were studied by electron microscopy in order to establish a possible correlation between the presence of virus particles and the susceptibility of mice to leukemia induction. An appreciable number of virus particles were found in megakaryocytes from C57BL mice injected with Graffi virus at birth. In these animals there was a high incidence of leukemia. Negative results on the presence of virus particles as well as leukemia induction were obtained in mice of the same strain injected with the virus at adult age. Similarly, with Gross Passage A virus injected at birth into both C3Hf/Gs and C57BL mice, virus particles were found in megakaryocytes from mice of the C3Hf/Gs strain which is susceptible to leukemia induction. Virus particles were not found in megakaryocytes from C57BL mice which are resistant to the leukemogenic action of this virus. PRESENCE DE PARTICULES VIRALES DANS LES MEGACARYOCYTES DE LA MOELLE OSSEUSE ET SENSIBILITE DES SOURIS A LA LEUCEMIE INDUITE PAR DES VIRUS Nous avons etudie au microscope electronique des megacaryocytes de moelle osseuse provenant de souris inoculees avec le virus de Graffi ou le virus de Gross au passage A, afin de voir s'il y avait une correlation possible entre la presence des particules virales et la sensibilite des souris a la leucemie provoquee. Nous avons trouve un nombre appreciable de particules virales dans les megacaryocytes de souris C57BL inoculees avec le virus de Graffi a la naissance. On a observe chez ces animaux une incidence elevee de la leucemie. Chez les souris de la měme souche ayant recu le virus a l'ǎge adulte, les resultats ont ete negatifs tant en ce qui concerne la presence de particules virales que l'induction d'une leucemie. De měme, apres injection de virus de Gross au passage A chez des souris C3Hf/Gs et C57BL a la naissance, on a trouve des particules virales dans les megacaryocytes des souris de la souche C3Hf/Gs qui est sensible a la leucemie provoquee. En revanche, on n'en a pas trouve avec la souche C57BL qui est resistante a l'action leucemogene de ce virus.

SUMMARY Application of the density gradient centrifugation technique for fractionation of mouse spleen cell suspensions to primate bone marrow, as a method to separate the immunocompetent cells from the haemopoietic stem cells to be grafted, resulted in a moderate but still fatal secondary disease in the recipient. Therefore, minor changes of the separation technique for primate bone marrow were necessary. Since adequate microscopic identification of the two cell types to be separated is not possible, assays for their functional characteristics had to be developed. The impracticability of in vivo assays in primates necessitates an investigation of in vitro properties of the immunocompetent cell and haemopoietic stem cell. With regard to the immunocompetent cells, the phenomenon of transformation of lymphoid cells by phytohemagglutinin was used. The reliability of this in vitro test, called phytohemagglutinin-response test, was ascertained by quantitative comparison with the graft-versus-host assay in vivo in mice in different cell suspensions under a variety of conditions. With regard to the in vitro test for haemopoietic stem cells, a method is described which appeared to be not specifically indicative for stem cells but, nevertheless has been found to be of value as a check on the reproducibility of the separation technique

The problem of antibody production and in general the internal regulation of the immune system was first focused by Jerne (1974) when he proposed a “network theory” based on internal antigenic properties of an idiotype.

Two patients with B chronic lymphocytic leukemia having leukemic cells that bind sheep red blood cells by different mechanisms are described. In the first case, rosette formation was mediated by the anti-sheep erythrocyte activity of a monoclonal surface IgMk, related to Forssman antigen. In the second, E-rosette formation was found to be independent of both surface immunoglobulins and the classic E-rosette receptor since the leukemic cells were recognized neither by the OKT-11 monoclonal antibody nor by other markers specific for T-cell lineage. Evaluation of these rare cases emphasizes that detection of surface immunoglobulins and spontaneous rosetting are not sufficient for the characterization of leukemic clones and raises some doubts concerning the use of available surface markers in the characterization of lymphoproliferative disorders.

The presence of Acetylcholine Receptor (AchR)-like structures on thymocytes raises the problem of its physiological role and of its possible impairment in Myasthenia Gravis (MG). In a murine ‘in vitro’ model a cholinergic ligand, succinylcholine, can inhibit spontaneous thymocyte proliferation and can stimulate cyclic AMP production. One monoclonal antibody (mAb), raised against Torpedo Californica AchR binding site, can interfere with the cholinergic ligand on cellular proliferation and cyclic AMP production. In conclusion, cholinergic ligands are able to specifically modify basic cellular functions of thymocytes through the presence of a functioning membrane AchR.

The recent literature on dental transplants in man and experimental models is reviewed. The histopathological and immunological aspects of the methods and results are critically analysed in function of the clinical applicability of this alternative to prosthesis. The different effects of mature tooth and germ transplants are considered in the light of experiments on various mammals, together with the contribution made by the various dental tissues to the taking of the transplant, and its acceptance or rejection by the host. Finally, questions associated with the establishment of a teeth bank and its potential creation of a sufficient supply of organs for transplantation are discussed.

Light-, electron microscopic and immunopathological findings in a nerve biopsy of a patient with peripheral neuropathy associated with monoclonal gammopathy are reported. Loss of fibers, Wallerian-like degeneration and segmental demyelination were the most important features observed in light microscopy. In E.M. widening of the peripheral lamellae of myelin sheaths and occasional aspects of hypermyelination were seen. Immunoperoxidase study showed binding of IgM (k light chain) on the myelin sheath. The possible pathogenetic implications of these findings are discussed.

Light-, electron microscopic and immunopathological findings in a nerve biopsy of a patient with peripheral neuropathy associated with monoclonal gammopathy are reported. Loss of fibers, Wallerian-like degeneration and segmental demyelination were the most important features observed in light microscopy. In E.M. widening of the peripheral lamellae of myelin sheaths and occasional aspects of hypermyelination were seen. Immunoperoxidase study showed binding of IgM (k light chain) on the myelin sheath. The possible pathogenetic implications of these findings are discussed.

Optimal conditions for in vitro histamine release mediated either by Con A (3 micrograms/ml) or by Ionophore A23187 (1 microgram/ml), were established for mouse peritoneal mast cells and human normal basophils. In both systems N-5' exerts potent inhibiting effects on histamine release after short term (1-5 minutes) in vitro preincubation. At concentrations of 1mM for mouse mast cells and 3mM for normal human basophils, N-5' inhibits up to 95% Con A-induced histamine release and more than 50% ionophore-induced histamine release. Such in vitro effects are more potent than DSCG-mediated inhibition, under similar experimental conditions, and are resistant to challenge with exceeding doses of the two releasing agents, particularly in the Con A system. Interestingly, basophils with apparent normal morphology, from a CML patient, were resistant to both challenges.

Normal fetal and postnatal thymuses, as well as thymuses from patients with myasthenia gravis (MG), were investigated by immunohistochemical and enzyme histochemical techniques and their morphology reviewed. Intrathymic B-cells, detected by ATPase activity, were found to be markedly increased in number in MG thymuses. They were scattered in the medulla and accumulated around the junctional and medullary vessels and Hassall’s corpuscles (HCs). Large epithelial cells, singly or within HCs, were found to be unevenly distributed in the medulla of all the thymuses examined. The striated muscle-like nature of some of these cells was revealed by the presence of myoglobin in their cytoplasm. In myasthenics these cells and small developing HCs characteristically surrounded lymph follicles and were in direct contact with the expanded cap of the follicle mantle, without interposition of reticulin fibres. The close association of immune reactive foci (lymphoid follicles, junctional and medullary vessels, and HCs) with structures involved in autoimmune responses in the thymus (muscle-like and true myoid cells, HCs) strongly suggests that the autoimmune reactions against AChR (acetylcholine receptor) and other muscular components, which constitute the basic defects in myasthenia gravis, may begin in the thymus.