A transplantation antigen, possibly of mitochondrial origin, that elicits rejection of parental strain skin grafts by F1 rats.
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Biomedical subjects
W K Silvers
Publications and source records attributed to W K Silvers.
Priming and cross-priming for H-Y in female mice.
Although female mice (H-2b and H-2g) that are responders to H-Y are able to cross-prime for this antigen, their ability to do so varies from strain to strain and can be influenced by whether they are exposed to H-Y via a subcutaneous hind footpad inoculation of male cells or via a male skin graft. On the other hand, females (H-2k) that are low responders to H-Y only can be sensitized to male skin isografts following a hind footpad inoculation of syngeneic male cells.
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Major histocompatibility complex restriction and cross-priming of H-Y antigen in rats.
Although female rats can be sensitized to H-Y-incompatible male skin isografts following exposure to MHC-incompatible male lymphoid cells, these cells are not as effective as MHC-compatible male cells. Evidence is presented that the effectiveness of the MHC-incompatible cells is a consequence of crosspriming and that such crosspriming only occurs if these cells are rejected.
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Major-histocompatibility-complex restricted and nonrestricted autoimmune effector mechanisms in BB rats.
To investigate whether the immunologic mechanisms of autoimmune pancreatic beta-cell destruction are MHC restricted, we examined the relative vulnerability of islet allografts from a panel of MHC-compatible and -incompatible donors to autoimmune damage after transplantation to spontaneously diabetic BB recipients. To circumvent a potentially confounding allograft response to the foreign islet graft, we utilized two strategies: (1) pretransplant in vitro culture of islets to delete intraislet APCs; and (2) induction of islet donor-specific immunologic tolerance in diabetes-prone BB rats. Experiments employing organ culture to prevent rejection demonstrated that MHC-incompatible grafts were significantly less vulnerable to autoimmunity than MHC-compatible grafts. In contrast, when we used the model of immunologic tolerance to exclude rejection, both MHC-compatible and -incompatible islet grafts were equally susceptible to autoimmune damage. The reason for this discrepancy has not been defined fully but may be related to our observation that tolerant BB animals exhibit increased peripheral blood NK-cell activity. NK cells are known to be cytotoxic to islets in vitro and could play a role in a non-MHC-restricted diabetogenic response in vivo. We conclude that both MHC-restricted and nonrestricted mechanisms are capable of contributing to anti-beta-cell autoimmunity in BB rats.
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Expression of major histocompatibility complex antigens on inflammatory peripheral nerve lesions.
The expression of major histocompatibility complex (MHC) antigens by cells of the rat peripheral nervous system (PNS) was studied using a model of peripheral nerve transplantation. Monoclonal antibodies to polymorphic determinants of MHC class I and class II (Ia) molecules were used to determine donor or recipient origin of MHC antigen-bearing cells in nerve allografts. The expression of class I and class II antigens by PNS parenchymal cells was modified during varying alloimmune conditions. Baseline, constitutive expression of class I antigens on endothelial and perivascular cells and class II antigens on interstitial cells were identified. Decreased MHC antigen expression was noted following in vitro culture of nerve allografts prior to implantation. After transplantation, enhanced donor-derived MHC antigen expression was demonstrated by both cultured and untreated allograft endothelial, perivascular and interstitial cells in a pattern which was distinct from isografts. This data supports a concept of perivascular monocytic and/or parenchymal cell (Schwann cell or resident macrophage-like cell) activity as the resident antigen-presenting cell for PNS immune processes.
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Major histocompatibility complex-unrestricted tolerance induction in rats.
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Regulation of pro-opiomelanocortin biosynthesis and processing by transplantation immunity.
It is more than thirty years since Billingham and Medawar showed that adrenocorticotrophic hormone (ACTH) and cortisol can prolong the survival of skin allografts. It has since become clear that glucocorticoid hormones are critically involved in the regulation of immunity. The level of glucocorticoids secreted in response to antigenic challenge corresponds to the magnitude of the immune response and in general reaches immunosuppressive levels. Interestingly, not all immune responses enhance ACTH and glucocorticoid hormone production. In transplantation immunity, the reverse seems to be true: circulating glucocorticoid levels at the time of skin graft rejection are lower than control levels. Because beta-endorphin and ACTH originate from the same prohormone, pro-opiomelanocortin (POMC), and are closely related in their tissue-specific processing and coordinate release, we have investigated the role of pituitary beta-endorphin in transplantation immunity. We report here that POMC biosynthesis and processing in the pars intermedia, but not in the anterior pituitary, can be regulated by T cell-specific factors secreted in animals undergoing transplantation immunity.
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Modulation of the major histocompatibility complex antigen and the immunogenicity of islet allografts.
Modulation of major histocompatibility complex (MHC) antigen by parenchymal cells and "passenger leukocytes" is a common feature of allograft rejection. To assess its significance we have examined the fate of antigen-presenting cell (APC)-depleted pancreatic islet allografts subsequent to increasing their expression of MHC antigens by in vitro exposure to the lymphokine interferon-gamma (gIFN). While most untreated grafts survived indefinitely, gIFN-exposed grafts were acutely rejected. Using in vitro islet cell-lymphocyte coculture assays, we attempted to dissect the underlying mechanism of enhanced islet cell immunogenicity resulting from gIFN treatment. We determined that gIFN exposure did not affect the capacity of islet cells to serve as APC for T lymphocytes, however islet cell exposure to gIFN was associated with enhanced vulnerability to allogeneic cytotoxic T lymphocyte (CTL) lysis in vitro by an CD5+ (OX-19+), CD8+ (OX-8+), CD4- (W3/25-), class I-restricted CTL. On the basis of these findings, we conclude that antigenic modulation can be a decisive factor in the survival of engrafted tissues by augmenting the interaction of the graft antigens with cytolytic effector T lymphocytes.
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The influence of interleukin 2 on the persistence of tolerance.
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Influence of the major histocompatibility complex (MHC) on the response to and expression of H-Y in rats.
The influence of the major histocompatibility complex (MHC) on the survival of H-Y-incompatible skin grafts in rats has been determined by challenging normal and previously sensitized females of various isogenic and congenic strains with male trunk or ear skin isografts. The MHC's influence on the potency of H-Y has also been evaluated by determining the survival of male parental strain ear skin grafts on sensitized (with F1 hybrid male cells) F1 hybrid females of two different MHC congenic strains. The results indicate that, as in mice, the MHC has a dual affect on H-Y; it is involved in determining the ability of females to respond to the antigen as well as influencing its potency.
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Elevated levels of a lymphocyte subset accurately predict the diabetic state in the BB rat.
The frequency of Ia antigen bearing W3/13 positive lymphocytes from the blood of 68 bio-breeding (BB) diabetes-prone rats was analyzed with monoclonal antibodies to determine whether elevated levels of these cells could predict which animals would subsequently become hyperglycemic. Selecting a value of greater than or equal to 4.00% as elevated, the sensitivity of this assay in predicting diabetes was 85%, while the specificity was 83%. We believe that elevated levels of Ia antigen bearing W3/13 positive lymphocytes reflect an ongoing immune process and accurately predict the likelihood of developing spontaneous hyperglycemia when obtained from a high risk population.
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Major histocompatibility complex (MHC) restriction of foreign transplantation antigens in rats rendered tolerant at birth.
Evidence is presented that MHC restriction of foreign transplantation antigens occurs when tolerance is induced. Whereas PVG and F344 rats rendered tolerant at birth with (DA X PVG)F1 and (DA X F344)F1 hybrid bone marrow cells (BMC), respectively, accept ACI skin grafts, presumably because the foreign transplantation antigens of these third party grafts, which are MHC-compatible with DA, are recognized only in association with the MHC of the hosts, DA rats rendered tolerant with (DA X PVG)F1 or (DA X F344)F1 hybrid BMC usually reject ACI skin. Further support that MHC restriction accompanies the induction of tolerance is provided by the observation that Lewis.1N rats rendered tolerant at birth with athymic (nude) Wag BMC are much more likely to accept BN.B2 (MHC-compatible with Wag) skin grafts, than BN (MHC-compatible with Lewis.1N) grafts.
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Immunogenicity and crossreactivity of specificity-associated markers on alloreactive T cells. Confirmation based on the model of tolerance abolition by adoptive transfer.
Syngeneic or parental strain T cells adoptively transferred into hybrid rats tolerant of third party alloantigens (L/DA tolerant of BN), in numbers insufficient to abolish tolerance, induce instead an active resistance to tolerance abolition with larger, usually effective dosages of donor cells. Of particular interest is the finding that immunization with T cells from one parental strain donor (e.g., DA) inhibited the tolerance-abolishing alloreactivity (anti-BN) of subsequently transferred T cells from the same (DA) and the other (L) parental strain donor. We conclude that anti-MHC receptors on T cells from different genetic backgrounds reactive to the same third party alloantigens share the same conserved immunogenic specificity-associated markers (SAM). The nonpolymorphism of anti-MHC receptors shown here in the transplantation tolerance model is a confirmation of the same conclusion drawn from earlier studies with the GVHD-resistance model, and it therefore suggests that these two models of T cell MHC interactions involve very similar mechanisms of T cell idiotypic regulation.
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Occurrence of donor Langerhans cells in mouse and rat chimeras and their replacement in skin grafts.
Evidence is presented that some endogenous Langerhans cells (LCs) may persist indefinitely in skin grafts. This evidence is based on the observation that although 2 weeks after grafting F1 hybrid mice and rats with genetically compatible skin, most of the LCs in the grafts were replaced with those of the host, some LCs of graft origin persisted for as long as the grafts were followed (154 days in mice and 249 days in rats). It has also been demonstrated that the spleen may be as good a source of LCs as the marrow. Thus, 6 weeks after lethally irradiated mice were restored with F1 hybrid spleen cells, most of the LCs in the epidermis of their pinnae were of donor origin. LCs of donor origin also were found in the epidermis of the pinnae of animals that had been inoculated at birth with spleen and lymph node cells (mice) or bone marrow cells (rats). Hence the occurrence of these cells provides another means of confirming that tolerance (chimerism) has been induced.
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Transplantation of cultured pancreatic islets to BB rats.
Pancreatic islets held in tissue culture before transplantation into artificially induced diabetics are not rejected. In animals and human identical twin transplants, the autoimmunity of naturally occurring diabetes may destroy islets, even if rejection is avoided. Therefore we studied whether autoimmune damage of islets can be avoided by pretransplant culture. Recipients were BB rats, which spontaneously developed diabetes. Donors were either Wistar Furth (WF) (major histocompatibility [MHC] identical to BB rats) or Lewis (MHC nonidentical to BB rats). Islets were inoculated into the portal vein either immediately after isolation or after 14 days in tissue culture (95% air, 5% CO2, 24 degrees C). Recipients of cultured islets received a single injection of 1 ml of antilymphocyte serum at the time of transplant. Recurrence of diabetes after transplantation of freshly isolated MHC incompatible Lewis islets occurred rapidly on the basis of rejection or autoimmune damage (or both). Precultured Lewis islets had prolonged or permanent survival. Freshly isolated MHC compatible WF islets were destroyed, and no improvement was seen with culture. We conclude that autoimmune destruction of transplanted islets can be avoided by tissue culture, as can rejection. This is important because this strategy is effective only if recipient and donor differ at the MHC locus. Islet donors may need to be selected on the basis of disparity of histocompatibility factors.
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Tolerance to parenchymal self. Regulatory role of major histocompatibility complex-restricted, OX8+ suppressor T cells specific for autologous renal tubular antigen in experimental interstitial nephritis.
BN rats develop interstitial nephritis after immunization with rabbit, but not rat renal tubular antigen. Using RT1n rat strains that differentially express tubular antigen, we investigated the unresponsiveness of BN rats to BN tubular antigen (BN-TBM) using delayed-type hypersensitivity (DTH) responses to BN-TBM as a measure of cell-mediated immunity. Our results indicate that rat strains expressing tubular antigen respond to immunization with BN-TBM with the clonal expansion of antigen-specific, cyclophosphamide-sensitive, OX8+, MHC-restricted suppressor T cells. Such suppression appears to be relevant to the maintenance of tolerance to parenchymal self, since chronic cyclophosphamide therapy abrogates suppression and results in significant interstitial nephritis.
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Distribution of ATPase-positive Langerhans cells in normal adult human skin.
The distribution of ATPase-positive Langerhans cells (LC) was investigated in 117 specimens of normal adult human skin and mucosa taken from different areas of the body. Although there were significant variations in the numbers of LC in each area examined, skin from the face and neck contained the highest density of cells (976 +/- 30.93/mm2). The densities of LC in trunk skin (740 +/- 28.97/mm2), scalp (693 +/- 69.56/mm2) and arm or leg skin (640 +/- 40.95/mm2) were similar. Buccal mucosa had significantly fewer LC (567 +/- 42.94/mm2) than trunk skin, and sacrococcyx skin and palm and sole skin displayed the smallest number of these cells (267 +/- 56.14/mm2 and, 189 +/- 19.15/mm2 respectively). No ATPase-positive LC were detected in the centre of two corneal specimens.
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The influence of T-lymphocyte precursor cells and thymus grafts on the cellular immunodeficiencies of the BB rat.
To determine whether abnormal T-lymphocyte precursor cells or an abnormal thymus is responsible for the immunologic deficiencies of spontaneously diabetic BB rats, thymus grafts or T-cell-depleted bone marrow cells were exchanged between diabetes-prone and non-diabetes-prone animals. Analysis of peripheral lymphocyte populations from these recipients with monoclonal antibodies, a fluorescence activated cell sorter, and mixed lymphocyte culture tests indicate that an abnormal thymus is not responsible for the immunodeficiency of BB rats, but that the defect resides within the lymphocyte precursor pool.
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