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Interferon gamma-treated keratinocytes activate T cells in the presence of superantigens: involvement of major histocompatibility complex class II molecules.

During inflammation in the skin keratinocytes can express major histocompatibility complex class II molecules but are unable to present nominal antigens to resting T cells. Certain bacteria including staphylococci produce a new class of antigens termed superantigens that are very potent T-cell activators. Using an in vitro model with cultured normal human keratinocytes and purified allogeneic T cells, we demonstrated that major histocompatibility complex class II+ keratinocytes can activate T cells in the presence of the superantigen staphylococcal enterotoxin B. Major histocompatibility complex class II+ keratinocytes activated T cells at concentrations of staphylococcal enterotoxin B as low as 100 pg/ml. The activation required contact between keratinocytes and T cells, was inhibited with a monoclonal antibody to human leukocyte antigen DR, -DQ, and was not affected by fixation of the keratinocytes. These data show that major histocompatibility complex class II+ keratinocytes activate T cells in the presence of the superantigen staphylococcal enterotoxin B.

Antibodies, Monoclonal↗

The effect of parental and maternal-fetal histocompatibility at MHC on sex ratio in offspring.

The secondary sex ratio (male births of total births) variation was investigated as a function of MHC antigens. Previous studies have indicated that at conception male zygotes are more frequent than female ones and abortions of male fetuses prevail. The present investigation addresses the question whether the histocompatibility relationships either between parents or between mother and offsprings may favor or hinder the outcome of pregnancy: particular combinations may cause distortions in the sex ratio. The results of the analysis of a sample of fertile families, demonstrate that, in first parities, female births are favored when parents share antigens at both HLA-A and -B loci (S.R. = 0.389), and mothers and fetuses share antigens at the HLA-B locus (S.R. = 0.222). The lack of antigens shared by parents at the three loci HLA-A, -B and -DR increases first male births (S.R. = 0.696). In the case of fetal maternal histocompatibility at DR locus only a slight, non-significant, increase in male first births (S.R. = 0.667) was observed. The effect of histocompatibility at HLA-B locus alone requires further investigation in order to assess the possible selective effect against male histocompatible embryos.

Embryo, Mammalian↗

Identification of an immunodominant mouse minor histocompatibility antigen (MiHA). T cell response to a single dominant MiHA causes graft-versus-host disease.

T cell responses to non-MHC antigens are targeted to a restricted number of immunodominant minor histocompatibility antigens whose identity remains elusive. Here we report isolation and sequencing of a novel immunodominant minor histocompatibility antigen presented by H-2Db on the surface of C57BL/6 mouse cells. This nonapeptide (AAPDNRETF) shows strong biologic activity in cytotoxic T lymphocyte sensitization assays at concentrations as low as 10 pM. C3H.SW mice primed with AAPDNRETF in incomplete Freund's adjuvant generated a potent anti-C57BL/6 T cell-mediated cytotoxic activity, and T lymphocytes from AAPDNRETF-primed mice caused graft-versus-host disease when transplanted in irradiated C57BL/6 recipients. These results (a) provide molecular characterization of a mouse dominant minor histocompatibility antigen, (b) identify this peptide as a potential target of graft-versus-host disease and, (c) more importantly, demonstrate that a single dominant minor antigen can cause graft-versus-host disease. These findings open new avenues for the prevention of graft-versus-host disease and should further our understanding of the mechanisms of immunodominance in T cell responses to minor histocompatibility antigens.

Amino Acid Sequence↗

Major histocompatibility complex class I deficiency prolongs islet allograft survival.

Because of islet allograft rejection, nonimmunosuppressed pancreatic islet allotransplantation has been unsuccessful for the treatment of type I diabetes. The role of major histocompatibility complex class I antigen expression on islet allograft survival was evaluated with the use of mice homozygous for a beta 2-microglobulin gene disruption. These mice express little if any functional major histocompatibility complex class I antigen. When these major histocompatibility complex class I-deficient islets were used as donors in an allogenic murine transplantation model, islet allograft survival was markedly prolonged. These results demonstrate a major importance for the alloresponse directed against major histocompatibility complex class I antigen.

Animals↗

Nerve allografts and histocompatibility in dogs.

The histocompatibility requirements for successful frozen nerve allografts were studied in 46 dogs. Major canine histocompatibility (DLA) differences appeared to be of vital importance for nerve regeneration and function, as judged by histological and electromyographic performance 7 to 9 months after grafting. Minor histocompatibility differences did not appear to lead to rejection of the frozen nerve allografts. Graft irradiation did not improve the acceptability of frozen DLA-mismatched grafts. The effect of DLA matching was much more pronounced in allografts 7 cm long than in allografts 4 cm long. The results indicate the need for a bank of frozen human histocompatible (HLA) nerve allografts, and a study of the effect of partial or complete HLA matching on their survival.

Animals↗

Skin-graft histocompatibility within Regional Poultry Research Laboratory inbred chicken lines.

Skin grafts were exchanged between specific-pathogen-free chicks within the Regional Poultry Research Laboratory (RPRL) inbred lines that are characterized for retrovirus susceptibility and immunogenetic traits. Lines 61 and 63 were histocompatible whereas lines 15I4 and 15I5 were nearly histocompatible. The RPRL Line 7(2) is only histocompatible within families at present, and line 100 has considerable heterogeneity for minor histoantigens. Reaseheath Line C (RH-C) has been established at the RPRL and its histocompatible. Numerous males in lines 6(1), 6(3), 15I4, and RH-C are able to reject female grafts containing the female-specific histoantigen. Two Ea-B alleles in 15I4 previously detected by blood-typing determined rapid skin graft rejection.

Animals↗

Cardiac allograft vasculopathy: relationship with acute cellular rejection and histocompatibility.

This article reviews the literature and summarizes the data obtained at Loyola University of Chicago about the relationship between rejection, histocompatibility, and cardiac allograft vasculopathy. Both the studies concerning the relationship between rejection and cardiac allograft vasculopathy and those evaluating the impact of histocompatibility on cardiac allograft vasculopathy have produced conflicting results. Most studies are retrospective and include a small number of patients followed up for short periods of time and treated with variable immunosuppressive regimens. In addition, the diagnosis of cardiac allograft vasculopathy is based on angiographic detection of coronary arterial abnormalities, a method that is known to underestimate the presence and severity of cardiac allograft vasculopathy. The ability to assess the impact of histocompatibility on the development of cardiac allograft vasculopathy is also limited by the lack of uniformity in the type and number of HLA variables analyzed, the extreme polymorphism of the HLA antigens and variability in serologic tissue typing techniques and quality. The results of our study suggest that complete mismatch at the HLA-B and -DR loci is associated with higher rejection rates and severity and with increased mortality. We also noted a trend toward a higher incidence of cardiac allograft vasculopathy in patients with complete mismatch at the HLA-DR locus. Future experimental and clinical studies should be done with use of molecular tissue typing techniques to further elucidate the impact of histocompatibility on cardiac allograft vasculopathy. The role of non-HLA antigens in the development of cardiac allograft vasculopathy requires further definition. Because in heart transplantation the short donor ischemic times compatible with a successful outcome limit the feasibility of prospective donor/recipient tissue typing, the development of immunosuppressive drugs that effectively reduce the detrimental effects of tissue incompatibility is crucially needed.

Adolescent↗

[HLA compatibility and susceptibility to habitual abortion. Results of histocompatibility testing of couples with frequent miscarriages].

We have performed class I HLA antigen testing in 42 women with recurrent habitual abortions and in their husbands. The main criterion for inclusion in this group was a frequency of more than two abortions without the known reasons for abortion and without a living child. 29 couples with a least two healthy children and no abortion in the clinical history served as a control group. The data were evaluated in respect to the association of HLA and disease as well as to the level of histocompatibility within the couples. In our results we did not find any significant association between HLA-A, B, C phenotypes and the habitual abortion. On the other hand, we observed a significantly higher level of histocompatibility in the couples with habitual abortions in comparison to the control couples. The frequency of identity in one and more histocompatibility antigens was in the patient group significantly higher than in the control group and as it could be expected by chance, calculated on the basis of antigen distribution within the loci A, B, C in the population in the southern part of the GDR. In no case we have revealed lymphocytotoxic antibodies as a possible cause for miscarriage. Our results are in favour of the hypothesis that a higher level of histocompatibility could be an immunological explanation for the habitual abortions. In addition, this hypothesis was supported by the successful immunotherapy with leukocytes derived from the husband or nonrelative donors.

Abortion, Habitual↗

Modulation of class I and class II histocompatibility antigens on human T cell lines by IFN-gamma.

IFN-gamma is an immunomodulatory agent which is known to induce or enhance the expression of class II histocompatibility Ag (Ia Ag) on many lymphoid cells and cell lines of diverse origin. However, we have observed that IFN-gamma did not induce the expression of Ia Ag on Ia- human T cell lines. Neither did IFN-gamma enhance the expression of Ia Ag on Ia+ T cells. However, IFN-gamma was able to enhance the expression of class I histocompatibility Ag (HLA-A,B,C Ag) on a number of the T cell lines tested. Experiments with 125I-labeled IFN-gamma showed a relatively small degree of specific binding to these T cell lines. More extensive studies on two of the T cell lines demonstrated 1000 and 2600 IFN-gamma binding receptor sites/cell and binding affinities of 4.0 X 10(-10) M and 7.3 X 10(-10) M. Thus, although IFN-gamma can bind to human T cell lines and enhance class I histocompatibility Ag on these cells, IFN-gamma alone does not appear to regulate expression of class II histocompatibility Ag on T cell lines.

Cell Line↗

Reduction of lethal graft-versus-host disease: transplantation of cultured murine bone marrow across minor histocompatibility differences.

The murine bone marrow culture technique was used to prepare donor marrow for bone marrow transplantation across minor histocompatibility complex differences. Previous studies have shown that theta-positive cells are rapidly lost from such cultures and that transplantation of cultured marrow across major histocompatibility complex differences results in a delay in the development of lethal graft-v-host disease (GVHD). In this study, a total of 1 to 2 X 10(7) nonadherent cells (740 to 1560 CFUs [colony-forming units]) from three-day-old cultures were used as a source of donor marrow. Three strain combinations were evaluated; LP/J into C57BL/6; BIO.BR into CBA/J; and C57BL/6 into LP/J. Donor mice were immunized with recipient spleen cells prior to culture in order to increase the graft-v-host response. For LP/J marrow into C57BL/6 mice, 5 X 10(7) donor spleen cells transplanted along with the marrow were needed to induce lethal GVHD. However, lethal GVHD was seen without the addition of spleen cells for BIO.BR into CBA/J and C57BL/6 into LP/J strain combinations. Most animals receiving fresh marrow were dead of GVHD five weeks after transplantation. With the use of cultured marrow the three-month survival was 80%, 51%, and 93%, respectively, for LP/J into C57BL/6, BIO.BR into CBA/J, and C57BL/6 into LP/J strain combinations. Long-term donor engraftment in all recipient animals receiving cultured marrow was confirmed by analyzing hemoglobin polymorphisms between the strain combinations. These results demonstrate that in contrast to transplantation across major histocompatibility complex differences, the use of cultured cells for bone marrow transplantation across minor histocompatibility complex differences allows for engraftment while reducing the risk of lethal GVHD.

Animals↗

Relationship between major histocompatibility antigens and disease. Possible associations with human arenavirus diseases.

Histocompatibility antigens, virus infections, and disease are discussed relative to avenues of research in humans with arenavirus infections. The data implicating a relationship between histocompatibility complexes in man and animals and diseases of the central nervous system are reviewed. Histocompatibility antigens may share common antigenic determinants with viruses, act as receptor sites for attachment of viruses, and be altered by viruses. In addition, genes regulating immune responses to a variety of natural and synthetic antigens are linked, in many species, to the major histocompatibility complex. Since injury associated with virus infections may be largely due to the activity of the immune system, study of immune response genes may provide insight into understanding resistance to disease. Further, histoincompatibility reactions can activate latent viruses with resultant disease.

Animals↗

Cellular interaction and the environment in lymphocyte development: the roles of antigen, histocompatibility, and growth factors in T cell-dependent B cell stimulation.

T cell-dependent B cell stimulation depends on cellular interactions between macrophages, T cells, and B cells. T cells recognize antigen in the context of Ia determinants on macrophages. This leads to the activation of helper T cells and to the production of helper factor(s) either by the activated helper T cells or by the macrophages. Cloned lines of helper T cells produce factors("help') for B cell replication and Ig secretion in the presence of histocompatible macrophages and of specific antigen. These factors stimulate histocompatible, as well as histoincompatible, mitogen-activated B cell blasts polyclonally. Thus, neither antigen nor histocompatibility, but antigen-unspecific, soluble factors are required to stimulate an activated B cell blast through the next round of division. Small resting B cells, however, are not stimulated to replication by these factors, but only to polyclonal, H-2-unrestricted maturation to Ig-secreting cells. Replication (and Ig secretion) of small resting B cells, however, is only induced when antigen-specific small B cells bind their specific antigen via surface Ig molecules and interact with histocompatible helper T cells. The preference of the resting B cells for such collaboration with T cell help is mapped to the K-end of the H-2 locus and probably constitutes the antigen expressed on B cells by the I region. It appears that a resting B cell is excited by the binding of specific antigen to surface Ig and by the interaction of its surface Ia with helper T cells. After this dual recognition the excited B cell can be stimulated by the antigen-unspecific factor(s) generated by the interaction of helper T cells, adherent cells and antigen to initiate growth. Immune induction of a B cell thus involves three controlling elements: Ig, Ia, and B cell growth factor receptors.

Animals↗

Histocompatibility in the rabbit. The effect of imbreeding on skin graft survival time.

Skin grafts were exchanged between siblings from 16 inbreeding lines of rabbits. Progressive inbreeding and genome fixation through 12 generations of brother X sister matings does not produce a concomitant increase in graft survival time but instead produces a heterogenous response reflecting the residual segregation of individual histocompatibility loci. Grafts exchanged between RL-A incompatible siblings were not maintained for more than 12 days, regardless of the degree of inbreeding. The frequency distributions of the survival times of grafts exchanged between animals from all inbreeding lines from each generation, F5 through F8, agree best with the expected values calculated by assuming that 17 independent histocompatibility loci, with 95% confidence limits of 11 and 28 loci, must be matched to assure acceptance of skin grafts for 60 days or more. However, in animals from line Sh5b, only 3 significant histocompatibility loci appear to be segregating. Two of the significant histocompatibility loci segregating in line Sh5b have not geen identified;the third significant locus is either the Hg blood group locus or is linked to the Hg locus. Established loci that remain polymorphic during intensive inbreeding may be important in the development of a model transplantation system; as inbreeding progresses these established loci may be maekers for histocompatiblity loci thathave a significant effect on allograft survival time.

Animals↗

Expression of intercellular and vascular cell adhesion molecules and class II major histocompatibility antigens in human lungs: lack of influence by conditions of organ preservation.

BACKGROUND: The expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and class II major histocompatibility complex antigens was studied in control lung tissue and preserved human donor lungs. The three controls were represented by wedge biopsy specimens taken from non-neoplastic lung surrounding bronchogenic carcinomas. METHODS: Nine lungs were harvested from six brain-dead donors, flushed with Euro-Collins solution or low potassium-dextran-glucose solution, and stored at 1 degree C or 10 degrees C. Samples of the latter organs were taken at the time of surgical harvest (baseline) and after 2, 12, 24, and 48 hours of preservation time. Immunostains with monoclonal antibodies against intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and class II major histocompatibility complex molecules were performed on all samples, and the relative presence of these determinants was evaluated. RESULTS: In both the controls and preserved lungs, intercellular adhesion molecule-1 expression was intense in the septal capillary endothelium and alveolar pneumocytes, but essentially absent in bronchial epithelium. Vascular cell adhesion molecule-1 was moderately to strongly labeled in the endothelia of large and small blood vessels of all types, and it was not seen in other cell types. Class II major histocompatibility complex antigens were variably observed in pulmonary epithelial cells, but they were not expressed by endothelia. There appeared to be no significant difference in the immunohistologic density of intercellular adhesion molecule-1 or vascular cell adhesion molecule-1 immunostaining in allografts at the specified time points of preservation; this conclusion was confirmed by Western blot analysis. Similar findings pertained to staining results for human leukocyte DR antigens. There was likewise no significant difference in the expression of the three analytes when donor lungs perfused with Euro-Collins solution versus low potassium-dextran-glucose solution were compared; this was also true of organs preserved at 1 degree C versus 10 degrees C. CONCLUSIONS: These results suggest that, in the immediate post-harvest period, modulations in the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, or class II major histocompatibility complex antigens in pulmonary allografts are not attributable to the influences of preservation conditions.

Adolescent↗

Chemical properties of two antigens controlled by the major histocompatibility complex of the chicken.

The chemistry of antigens controlled by the major histocompatibility complex of the chicken has been investigated. Peripheral blood leukocytes of five chicken strains were radioactively labeled by incorporation of tritiated amino acids, enzymatic iodination, or mild periodate oxidation followed by reduction with tritiated sodium borohydride. Membrane-bound antigens were solubilized with Nonidet P-40 and purified by a two-step immunoprecipitation procedure. The resulting immunoprecipitates were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing or nonreducing conditions. The chicken major histocompatibility antigens (B antigens) are composed of polypeptide chains with molecular weights (in the reduced form) of 40,000 to 43,000 and 11,000 to 12,000, as deduced from their mobilities in internally calibrated gels. The larger chains, when isolated from different chicken strains, can have slightly different mobilities in such gels; thus the mobilities of the large polypeptides from strains WA and WB correspond to molecular weights of 40,000 and 43,000, respectively. Gels run under nonreducing conditions give similar results; in particular no dimers or oligomers of the larger chains are detectable, thus ruling out an immunoglobulin-like structure for the B antigens. The large chains are labeled by the periodate oxidation-reduction procedure, suggesting that they are glycoproteins (probably containing sialic acid), while the small polypeptides cannot be labeled by this method. An additional protein or proteins of apparent molecular weight about 30,000 could be precipitated from 3H-amino-acid-labeled leukocyte lysates by one particular anti-B serum. This protein(s), named B-L, differs from the B major histocompatibility antigens in that it is not associated with the small chain of molecular weight 11,000 to 12,000 and does not occur on erythrocytes. Thus, at least two protein chains are coded for (or have their synthesis controlled by) genes in the chicken major histocompatibility complex.

Animals↗

Minors come of age: Minor histocompatibility antigens and graft-versus-host disease.

Minor histocompatibility antigens (miHA) are responsible for the occurrence of graft-versus-host disease in the setting of a major histocompatibility complex matched sibling allogeneic stem cell transplantation. These miHA are peptide fragments that are associated with major histocompatibility complex class I or class II antigens. Elegant experiments have led to the molecular characterization of these antigens. Efforts to prevent graft-versus-host disease could be targeted through this pathway by matching for these miHA or by preventing antigen recognition. Alternatively, these miHA could be exploited as targets for a more potent graft-versus-malignancy effect. This area of miHA promises to continue to be an exciting area of continued research.

Antigen Presentation↗

Responses against antigens encoded by the H-3 histocompatibility locus: antigens stimulating class I MHC- and class II MHC-restricted T cells are encoded by separate genes.

The purpose of this work was to study the genetic basis of histocompatibility antigens encoded by the mouse minor histocompatibility (H) locus H-3. Both class I major histocompatibility complex (MHC)-restricted cytotoxic T lymphocytes (CTL) and class II MHC-restricted helper T cells (TH) specific for antigens encoded by genes within the H-3 locus were isolated and analyzed. Typing a number of mouse strains for expression of antigens recognized by these TH and CTL suggested that there was a different strain distribution pattern of expression of the antigens recognized by TH compared with those recognized by CTL. Separation of the genes whose products stimulate TH from those whose products stimulate CTL was suggested by: (1) analysis of the strain B10.FS(92NX)/Grf that has undergone recombination within the H-3 region; (2) genetic segregation studies of (B10.UW-H-3b/Sn x C57BL/10Sn)F2 mice; and (3) F1 complementation studies in which CTL specific for products of the TH-defined gene(s) could not be detected, even in the absence of immune responses to products of the CTL-defined genes. Taken together, these data suggest that in addition to two genes (B2m and Cd-1) within the H-3 region whose products typically stimulate class I MHC-restricted CTL, there is at least one additional gene whose product selectively stimulates class II MHC-restricted TH. This new gene is located telomeric from the CTL-defined genes and between the loci we and un on chromosome 2. These data demonstrate a novel degree of complexity of the H-3 "locus" and suggest selective presentation of minor H gene products in the context of class I or class II MHC proteins.

Animals↗

A CD8 DE loop peptide analog prevents graft-versus-host disease in a multiple minor histocompatibility antigen-mismatched bone marrow transplantation model.

Donor CD8(+) T cells can be potent mediators of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation to either major histocompatibility complex (MHC) class I-or multiple minor histocompatibility antigen-mismatched recipients. To develop small molecular inhibitors of CD8(+) T-cell activity, theoretical structural analysis of the human CD8 alpha molecule was previously used to identify potential functional surface epitopes that interact with the MHC class I molecule. The DE loop (p71-78) was identified as such a target region, and a panel of synthetic cyclized peptide mimics of this region were tested for their inhibitory effects on cytotoxic T lymphocyte activity in human cell-mediated lympholysis assays. Peptide 1109 (CKRLGDTFVC) was most effective at inhibiting specific target cell lysis. Accordingly, studies were conducted to determine whether there was sufficient cross-species homology in the DE loop region and its nonpolymorphic interactive site on the beta(2)-microglobulin domain of the MHC class I molecule to allow similar inhibition of murine CD8(+) cytotoxic T lymphocyte activity. On the basis of strong in vitro inhibitory activity of 1109 in the murine system, the capacity of the peptide to inhibit in vivo CD8(+) T-cell effector functions in skin and hematopoietic stem cell transplantation models was examined. In the C57BL/6 anti-bm1 skin allograft rejection model, across an MHC class I barrier, a single injection of 1109 at the time of transplantation significantly prolonged graft survival. Moreover, 1109 administered at the time of transplantation in the multiple minor histocompatibility antigen-disparate B10.BR-->CBA GVHD model significantly prolonged the survival of lethally irradiated mice that underwent transplantation with donor bone marrow cells and CD8(+) T cells. Histopathologic analysis confirmed that mice treated with the synthetic peptide exhibited diminution of epithelial target cell injury. Specificity of the peptide effect was evidenced by draining lymph node cells from B10.BR mice that had been challenged with CBA lymphocytes and simultaneously treated with 1109. These cells could not generate secondary proliferative responses in vitro upon stimulation with CBA splenocytes but could respond to third-party C57BL/6 stimulation. Thus, the 1109 peptide has potential application in the prevention of CD8-mediated GVHD development.

Amino Acid Sequence↗