Mechanisms of transplantation tolerance: do anti-idiotypic antibodies play a role?
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Animals↗
Biomedical subjects
W M Kast
Publications and source records attributed to W M Kast.
Treatment with monoclonal anti-CD3 antibody protects against lethal Sendai virus infection by induction of natural killer cells.
C57BL/6 mice are protected from a lethal pneumonia caused by Sendai virus when treated with low doses of mAb directed to the CD3 Ag. The protective mechanism is not due to an accelerated Sendai virus-specific Th cell, CTL, or antibody response but to a strong NK cell response via the in vivo induction of lymphokines. Antibodies directed against the NK1.1 and asialo GM1 marker totally reversed the protective effect of anti-CD3 treatment. In vivo treatment with rIL-2 also induced NK activity and induced antiviral protection. Treatment with anti-CD3 protects when given in a narrow time window (1 day before until 1 day after Sendai virus inoculation), indicating that NK activity is protective in the early phase of virus infection.
Animals↗
Direct binding of peptide to empty MHC class I molecules on intact cells and in vitro.
MHC class I molecules devoid of peptide are expressed on the cell surface of the mouse mutant lymphoma cell line RMA-S upon culture at reduced temperature. Empty class I molecules are thermolabile at the cell surface and in detergent lysates, but can be stabilized by the addition of presentable peptide; peptide binding appears to be a rapid process. Furthermore, class I molecules on the surface of RMA-S (H-2b haplotype) cells cultured at 26 degrees C can efficiently and specifically bind iodinated peptide presented by H-2Kb. Binding of iodinated peptide is also observed at a lower level for nonmutant cells (RMA) cultured at 26 degrees C. These experiments underscore the role for peptide in maintenance of the structure of class I molecules and, more importantly, provide two assay systems to study the interactions of peptides with MHC class I molecules independent of the availability of T cells that recognize a particular peptide-MHC class I complex.
Animals↗
Induction of transplantation tolerance by intravenous injection of allogeneic lymphocytes across an H-2 class II mismatch. Different mechanisms operate in tolerization across an H-2 class I vs. H-2 class II disparity.
Previously, we have shown that the intravenous (i.v.) injection of allogeneic lymphocytes across an H-2 class I-mutant disparity leads to specific skin allograft tolerance caused by irradiation-sensitive donor T cells, which function as veto cells. In the present study, we show that the i.v. injection of H-2 class II-incompatible spleen cells also results in specific skin allograft tolerance. However, tolerance induction depends on the presence of irradiation-resistant non-T cells in the donor cell inoculum. Thus, different mechanisms operate in tolerance induction across an H-2 class I vs. H-2 class II mismatch. I.v. injection of allogeneic spleen cells across an H-2 class I plus class II disparity does not result in skin allograft tolerance. Finally, our data show that transfusion-induced suppression of the delayed-type hypersensitivity response against alloantigens does not correlate with skin allograft tolerance induced by i.v. injected allogeneic lymphocytes. In conclusion, the type of H-2 mismatch between transfusion donor and recipient not only determines the occurrence of allograft tolerance but also the mechanism leading to tolerization.
Animals↗
Association between the cellular p53 and the adenovirus 5 E1B-55kd proteins reduces the oncogenicity of Ad-transformed cells.
The association of the cellular p53 protein with the E1B-55kd protein of adenovirus 5 (Ad5) is thought to result in inactivation of the p53 recessive oncogene product. Here we show that Ad5 E1-transformed 3Y1 rat cells which express low levels of the 55 kd E1B protein do not contain the p53-E1B 55kd complex. These cells have nuclearly located p53 and are highly oncogenic in nude mice. In 3Y1 cells expressing the E1B protein at a sufficiently high level, association between p53 and E1B-55kd occurs, resulting in an almost complete trapping of p53 into a discrete cytoplasmic body. These cells only form tumors after a very long latency period and in the tumors that eventually appear selection has occurred in favor of cells lacking the complex and containing free nuclear p53. Comparable results were found when highly oncogenic Ad12-transformed cells were supertransfected with the Ad5 E1B region. In none of the Ad-transformed mouse, rat and human cell lines examined, could we detect p53 of abnormal molecular weight or association with hsc70, neither could we immunoprecipitate p53 by the mutant specific antibody PAb240. These data suggest that a high level of nuclear p53 with a wild-type conformation contributes to the oncogenicity of Ad transformed cells.
Adenovirus Early Proteins↗
Different requirements for the regulation of transplantation tolerance induction for allogeneic versus xenogeneic major histocompatibility complex antigens.
One way to solve the problem of human donor organ shortage is the use of animal organs. Therefore, it is important to study the T-cell response against xenogeneic major histocompatibility complex (MHC) antigens. In the present study, we have used HLA-B27 transgenic mice in a xenogeneic transplantation model. The results indicate that both transgenic skin transplantation and intravenous (IV) injection of transgenic spleen cells can reverse specific T-cell low responsiveness against the transgenic HLA-B27 antigen into high responsiveness in vivo and in vitro. In contrast, IV injection of spleen cells across an allogeneic H-2 class I disparity results in transplantation tolerance. Thus, despite T-cell low responsiveness against the transgenic HLA-B27 antigen, IV injection of transgenic HLA-B27 disparate lymphocytes does not tolerize, but rather immunizes for the xeno-MHC antigen.
Animals↗
Efficacy of cytotoxic T lymphocytes against virus-induced tumors.
Cytotoxic T lymphocytes (CTLs) against virus-induced tumors are highly effective mediators of tumor-specific immunity in vivo. CTLs bearing the surface molecule CD8 recognize small (approximately 10-amino-acid) viral peptides that are presented in association with major histocompatibility (MHC) class I molecules at the surface of tumor cells. In the case of mouse tumors induced by the early region (E1) of human adeno-virus type 5 (Ad5), cloned CD8+ CTLs directed against a peptide derived from the viral nuclear oncogene product E1A can rapidly eradicate large established tumors, provided that interleukin-2 (IL-2) is given simultaneously. Similar findings have been reported for other virus-induced tumors. Conceivably, adoptive therapy with CD8+ CTLs could be extended to tumors that originate in other ways, including those arising through activation or mutation of cellular oncogenes.
Adenovirus Early Proteins↗
Eradication of adenovirus E1-induced tumors by E1A-specific cytotoxic T lymphocytes.
Cytotoxic T lymphocyte (CTL) clones against adenovirus type 5 (Ad5) early region 1 (E1)-transformed cells were generated in C57BL/6 (B6) mice. A defined peptide encoded by Ad5 E1A is the target structure for H-2Db-restricted CTLs. Upon intravenous injection into B6 nude mice bearing Ad5 E1-induced tumors, these CTLs, if combined with recombinant IL-2, destroy subcutaneous tumor masses up to 10 cm3. The in vivo action of CTLs is highly specific, and long-term "memory" persists in treated nude mice months after tumor regression. Our data show an important role for CTLs directed against a viral nuclear oncogene product in tumor eradication.
Adenoviridae Infections↗
Lack of correlation between levels of MHC class I antigen and susceptibility to lysis of small cellular lung carcinoma (SCLC) by natural killer cells.
Small cellular lung carcinoma (SCLC) cell lines are susceptible to lysis by NK cells. SCLC, normally negative for MHC class I Ag, were rendered positive for HLA-A and -B Ag by two methods: treatment with IFN-gamma or transfection with HLA class I genes. Exposure to IFN-gamma induced high levels of class I Ag and reduced susceptibility to NK-mediated lysis. However, transfection with either HLA-A2, HLA-B27, or HLA-B27 with beta 2m did not result in reduced susceptibility to NK cells. These transfectants expressed amounts of HLA class I Ag comparable to those in IFN-gamma-treated, untransfected cells. Transfection with the beta 2m gene or plasmid alone neither influenced levels of surface class I Ag nor resulted in reduced susceptibility to lysis by NK cells. Thus, the effects of IFN-gamma on NK susceptibility can be dissociated from the induction of class I Ag.
Carcinoma, Small Cell↗
Allograft tolerance induction in adult mice associated with functional deletion of specific CTL precursors.
Rejection of H-2 class I bm 1 mutant skin allografts by B6 recipient mice is mediated by a population of CD8+ anti-bm1 cytotoxic T-lymphocytes that produces and consumes its own T helper factor in response to bm1 skin allografts (dual function CTL). Previously we have demonstrated that transfusion of allogeneic lymphocytes across an H-2 class I disparity induces specific long-lasting skin allograft survival. We now show that intravenous injection of allogeneic spleen cells across the bm1 mutant disparity results in a temporary decrease of donor-reactive CTLp in the spleen of recipient mice, lasting for approximately five weeks. The sponge matrix allograft model was used to show that allograft tolerance is caused by a specific functional clonal deletion of CTLp within the allograft. We propose that dual function CTL are vetoed by donor T cells, resulting in skin allograft tolerance.
Animals↗
Immunosurveillance of virus-induced tumors.
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Adenoviruses, Human↗
Transfusion-induced skin allograft enhancement across an H-2 class-I mismatch is caused by a clonal deletion of donor-specific cytotoxic T-lymphocyte precursors within the allograft.
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Animals↗
Failure or success in the restoration of virus-specific cytotoxic T lymphocyte response defects by dendritic cells.
C57BL/6 (B6, H-2b) mice are CTL responders to both Sendai virus and Moloney leukemia virus. In the former response the H-2Kb class I MHC molecule is used as CTL restriction element, in the latter response the H-2Db molecule. B6 dendritic cells (DC) are superior in the presentation of Sendai virus Ag to CTL in comparison with B6 normal spleen cells. Con A blasts have even less capacity to present viral Ag than NSC, and LPS blasts show an intermediate capacity to present viral Ag. H-2Kb mutant bm1 mice do not generate a CTL response to Sendai virus, but respond to Moloney leukemia virus, as demonstrated by undetectable CTL precursors to Sendai virus and a normal CTL precursor frequency to Moloney virus. Compared to B6 mice, other H-2Kb mutant mice show decreased Sendai virus-specific CTL precursor frequencies in a hierarchy reflecting the response in bulk culture. The Sendai virus-specific CTL response defect of bm1 mice was not restored by highly potent Sendai virus-infected DC as APC for in vivo priming and/or in vitro restimulation. In mirror image to H-2Kb mutant bm1 mice, H-2Db mutant bm14 mice do not generate a CTL response to Moloney virus, but respond normally to Sendai virus. This specific CTL response defect was restored by syngeneic Moloney virus-infected DC for in vitro restimulation. This response was Kb restricted indicating that the Dbm14 molecule remained largely defective and that a dormant Kb repertoire was aroused after optimal Ag presentation by DC. In conclusion, DC very effectively present viral Ag to CTL. However, their capacity to restore MHC class I determined specific CTL response defects probably requires at least some ability of a particular MHC class I/virus combination to associate and thus form an immunogenic complex.
Animals↗
Mechanism of skin allograft enhancement across an H-2 class I mutant difference. Evidence for involvement of veto cells.
Intravenous injection of spleen cells across mutant class I H-2 incompatibility results in a drastic donor-specific prolongation of skin allograft survival and a marked decrease in the donor-specific cytotoxic T lymphocyte precursor (CTLp) frequency. This immunosuppressive effect depends on the presence of radiosensitive T cells in the donor cell inoculum. It was excluded that a graft-vs.-host reaction was responsible for the observed effects. In mixing experiments, spleen cells from animals transfused with allogeneic lymphocytes could not suppress a normal CTL response against the alloantigen, despite an excess of putative recipient-derived spleen suppressor cells. The data are compatible with the idea that donor T cells function as veto cells which inactivate recipient CTLp directed against the alloantigen expressed by the veto cell.
Animals↗
Dendritic cells and antigen presentation in the regulation of cytotoxic T lymphocyte responses against viruses and transplantation antigens.
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Animals↗
Thymic immune response gene function in radiation chimeras reconstituted with purified hemopoietic stem cells.
Thymectomized (C57BL/6[B6] X bm1)F1 mice and thymectomized (B6 X bm12)F1 mice were engrafted with neonatal parental thymus of either B6 type [H-2b mouse, Sendai virus cytotoxic T cell (Tc) responder] or bm1 type (H-2Kb mutant, Sendai virus Tc nonresponder) and B6 type (H-Y Tc responder) or bm12 type (H-2 I-Ab mutant, H-Y Tc nonresponder), respectively. All mice were irradiated and reconstituted with highly purified syngeneic pluripotent hemopoietic stem cells. All types of thymus engraftment resulted in a restored T cell immunocompetence. The Tc reaction to Sendai virus in (B6 X bm1)F1 mice engrafted with both responder type B6 and nonresponder, type bm1 neonatal thymus allowed maturation of Sendai-specific, H-2Kb-restricted Tc. For the Tc reaction to H-Y, only responder type B6 thymus restored the Tc response, whereas this was not achieved with nonresponder type bm12 thymuses. We conclude from this study that in this radiation stem cell chimera system the radioresistant component of the thymus dictates major histocompatibility complex (MHC) specificity and immune response phenotype of T cells restricted to class II MHC molecules but not of T cells restricted to class I MHC molecules.
Animals↗
Cooperation between cytotoxic and helper T lymphocytes in protection against lethal Sendai virus infection. Protection by T cells is MHC-restricted and MHC-regulated; a model for MHC-disease associations.
The in vivo importance of class I MHC regulation of the Tc response to a natural pathogenic agent of high virulence was studied on the basis of our previous demonstration of a major difference in the capacity to generate a Sendai virus-specific Tc response between C57BL/6 (B6, H-2b) mice and H-2Kb mutant B6.C-H-2bm1 (bm 1) mice. These two mouse strains differ from each other only in three amino acids in the crucial H-2Kb restriction element for this response. bm 1 mice, in contrast to B6 mice, are Tc nonresponders against this virus, but show Sendai-specific T cell proliferation, antibody production, and DTH reactions, as well as NK cell activity, equal to those of B6 mice. B6, Sendai Tc-deficient bm 1 and T cell-deficient B6 nu/nu mice differ from each other in susceptibility to lethal pneumonia induced by i.n. inoculation of virulent Sendai virus. The lethal dose (LD50) in B6 mice averaged 152 TCID50, in bm 1 mice, 14 TCID50 and in B6 nu/nu mice 0.5 TCID50. The importance of Tc was also shown by the complete protection of B6 nu/nu mice against infection with a lethal virus dose by i.v. injection of a Sendai virus-specific, IL-2-dependent and H-2Kb-restricted B6 Tc clone. In vivo protection by this Tc clone was H-2Kb-restricted. Apart from Tc, an important role for virus-specific Th cells is evident from the difference in susceptibility between bm 1 and B6 nu/nu mice. This conclusion was supported by the demonstration that the mean survival time of B6 nu/nu and bm 1 nu/nu mice could be significantly prolonged, in an I-Ab-restricted manner, by the injection of in vitro-propagated, Sendai-specific B6 or bm 1 Th clones after a lethal dose of Sendai virus, and by the demonstration that inoculation of these Th clones provided help to virus-specific Tc by means of IL-2 production. Strikingly, Th and Tc cooperate in anti-Sendai virus immunity, since permanent survival of lethally infected nu/nu mice was only achieved by inoculation of a mixture of Tc and Th clones or a mixture of a Tc clone and rIL-2. This study provides a unique model for the study of MHC-disease associations.
Animals↗
Alternative splicing in the mouse H-2Kd gene is not necessary for the classical Kd antigen function.
The mouse H-2Kd gene gives rise to several transcripts by alternative splicing. In addition to encoding the known Kd antigen, it could thus encode at least one minor hypothetical Kd-like molecule, with a distinct NH2 terminus. The existence of this "24" product can be inferred from a cDNA clone which was previously isolated. We have engineered both this cDNA and its canonical counterpart into a eukaryotic expression vector. After transfer of these constructs into mouse fibroblasts, we obtained cells expressing either one of the transcripts, but not both. In cytotoxicity tests, we found no expression of the "24" product on the cell surface, nor did we obtain any clue concerning its function. In contrast, cells which express Kd antigen, but none of the possible Kd-like molecules produced by alternative splicing, were functional in all aspects examined. We conclude that alternative splicing does not contribute to the known function of the Kd antigen.
Animals↗