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S F Oluwole

Publications and source records attributed to S F Oluwole.

At least 19 recordsLinked to original sources
PubMed1997

Dependence of acquired systemic tolerance to rat islet allografts induced by intrathymic soluble alloantigens on host responsiveness, MHC differences, and transient immunosuppression in the high responder recipient.

Recent studies suggest that the adult immune system can be manipulated by intrathymic (IT) inoculation of donor Ag to accept cardiac and islet allografts in the low responder rat combination of Lewis-to-WF. We have now extended this study to examine the effect of IT inoculation of soluble protein Ag obtained from 3M KCl extracts of resting T cells combined with transient ALS immunosuppression on islet allograft survival in the high responder combination of WF-to-Lewis. We first confirmed the earlier observation that IT injection of 2 mg soluble Ag on day -7 led to permanent islet graft survival (>200 days) in the Lewis-to-WF rat combination without the use of recipient immunosuppression and found this to be true in the Lewis-to-ACI rat combination. In the high responder combination of WF-to-Lewis, unmodified Lewis rats pretreated with IT inoculation of 2 mg soluble Ag acutely rejected WF and BN islet allografts. IT inoculation of donor Ag combined with 1 ml ALS transient immunosuppression on day -7 led to a modest graft prolongation [24.8+/-10.1 days as compared with 15.2+/-3.6 days in ALS only treated controls]. Intrathymic injection of soluble Ag on day -7 combined with 1 ml ALS on days -7 and 0 relative to allografting resulted in 100% permanent islet graft survival (>200 days) compared with an MST of 20.6+/-2.3 days in ALS only-treated controls. Similar treatment led to acute rejection of 3rd party (BN) grafts, thus demonstrating donor-specificity. In addition, extrathymic inoculation of donor Ag in similarly immunosuppressed animals did not result in islet graft prolongation, once again confirming the importance of the thymus in tolerance induction. To examine them for donor-specific tolerance, long-term unresponsive (>120 days) Lewis recipients of renal subcapsular islets underwent nephrectomy of the islet bearing kidneys and were challenged with intraportal donor- or third party-type islets after becoming diabetic. All the nonimmunosuppressed recipients of donor-type (WF) islets became permanently normoglycemic (>100 days) while the third-party (BN) grafts were promptly rejected, with an MST of 10.6 days. These findings confirm that acquired thymic tolerance induced by IT inoculation of soluble protein Ag in the low to moderate responder rat combinations is reproducible in the high responder combination provided that adequate peritransplant immunosuppression is used. This study suggests that acquired thymic tolerance in the rat model is dependent on host responsiveness to alloantigens, MHC differences between the donor-recipient pair, and the use of transient immunosuppression in the high responder recipient. This model may have potential clinical application in the development of strategies for specific transplantation tolerance.

Animals↗
PubMed1996

Acquired systemic tolerance to rat cardiac allografts induced by intrathymic inoculation of synthetic polymorphic MHC class I allopeptides.

This study extends the finding that intrathymic (IT) injection of 3M KC1 extracts of T cells induces transplant tolerance to the use of well defined polymorphic MHC class I allopeptides derived from the hypervariable domain of RT1.Au (WF MHC class I). While three of the six synthetic RT1.Au peptides were immunogenic, three others were nonimmunogenic when tested in ACI responders. In our initial studies, we examined the effects of IT injection of a mixture of equal concentrations of the three nonimmunogenic RT1.Au peptides on WF cardiac allograft survival in ACI recipients. The results showed that a single IT injection of 100 and 300 microg class I MHC allopeptides on day -7 relative to cardiac transplant did not significantly prolong graft survival in naive ACI recipients (MST of 9.8, and 12.3 days vs. 10.5 days in controls). In contrast, 600 microg allopeptides injected IT resulted in modest prolongation of graft to an MST of 19.5 days. However, IT injection of 600 microg allopeptides combined with 0.5 ml ALS on day -7 led to permanent acceptance (>200 days) of cardiac allografts in 7/9 ACI recipients compared with survival of 24.2 days in ALS alone treated controls. In contrast, similar treatment led to acute rejection of third party (Lewis) cardiac allografts. Intravenous injection of 600 microg allopeptides combined with ALS did not result in prolonged graft survival (26.8 days). The long-term unresponsive ACI recipients (>100 days) challenged with second-set cardiac grafts accepted permanently donor-type (WF) grafts while rejecting the third party (Lewis) grafts, a finding that confirms acquired systemic tolerance. These findings confirm the role of IT injection of synthetic polymorphic allopeptides in the induction of acquired thymic tolerance and provide the rationale for testing this strategy in large animals and eventually in man.

Amino Acid Sequence↗
PubMed1996

UVB irradiation of human-derived peripheral blood lymphocytes induces apoptosis but not T-cell anergy: additive effects with various immunosuppressive agents.

UVB irradiation of bone marrow or pancreatic islets has been shown to prevent GVHD and to induce transplant tolerance in experimental animal models. To clarify the underlying mechanism(s) responsible for these UVB effects we have examined in vitro cell function following UVB irradiation using LDA, FACS analysis, and DNA gel electrophoresis to assess the role of UVB-induced anergy and/or cell death. To extend our studies to the clinical setting and to promote chimerism and tolerance to organ allografts, we have further studied the effects of UVB irradiation combined with the commonly used immunosuppressive agents (cyclosporine, azathioprine, and methylprednisolone) on human T cells in proliferative in vitro assays. When cytotoxic and proliferative responses to allogeneic cells or to PHA stimulation were evaluated in LDA, the use of increasing doses of UVB irradiation resulted in a dose-dependent decrease in proliferative and cytotoxic responses of T-cells as seen by decreases in precursor frequencies. The results of proliferative T-cell assays suggest an additive immunosuppressive effect of various immunosuppressive drugs when combined with UVB irradiation. Gel electrophoresis of DNA derived from resting and activated, UVB-irradiated PBLs showed apoptosis at all UVB doses used. FACS analysis of UVB-treated CD2+ cells resulted in a UVB dose-related decrease in cell numbers that correlated with viability studies. It appears that UVB irradiation of both activated and resting PBLs induces programmed cell death but not anergy of T-cells.

Apoptosis↗
PubMed1996

UVB-irradiation of human bone marrow: potential for donor specific tolerance.

Bone marrow mononuclear cell (BMMC) transplant may serve to produce donor specific tolerance for a coincident solid organ graft, but with the risk of graft versus host disease (GVHD). We examined in vitro the immunomodulatory effect of UVB on human BMMCs as potential prophylaxis against GVHD for clinical transplantation. After 10-200 J/m2 UVB-irradiation, BMMCs were examined by proliferative response (in mixed lymphocyte reaction and following phytohemagglutinin stimulation) and by cytokine profile. We also evaluated CFU-GM, CFU-GEMM, and BFU-E progenitor viability by 2-week methyl cellulose cultures following UVB-irradiation. Parallel studies were applied to marrow that was T-cell depleted by soybean agglutination (SBA) or by SBA and sheep erythrocyte rosetting (SBA-E-). We found that (1) UVB produces a dose-dependent inhibition of the proliferative response to stimulators by human BMMCs; (2) increasing doses of UVB-irradiation and increasing levels of T-cell depletion (TCD) are both inversely related to production of lymphokines (IL2, IL3, LIF, IFN-gamma, and GMCSF) and (3) T-cell depletion, but not UVB-irradiation, decreases the production of monokines (IL1, TNF, IL6). Progenitor cell viability was decreased but preserved at 100 J/m2 of UVB. Our findings suggest that UVB compares favorably with TCD as a technique for inhibition of GVHD and therefore that UVB-modulation of bone marrow (BM) inoculum may be useful in the prevention of GVHD in clinical bone marrow transplantation accompanying a solid organ graft.

Bone Marrow↗
PubMed1996

The mechanism of UVB prevention of graft versus host disease.

We have previously demonstrated that Ultraviolet B (UVB) irradiation of Lewis donor bone marrow (BM) allografts prevents graft versus host disease (GVHD) in ACI recipients while allowing full engraftment. In a one-way GVHD model of parent to Lewis X BN (F1) rats, the site and mechanism of the action of UVB irradiation was assessed by adding nonirradiated isolated cell subsets, isolated by monoclonal antibodies (Mab) to cell surface markers, to the reconstituting UVB-irradiated bone marrow inoculum. GVHD was assessed primarily on clinical grounds by observation of posture, alopecia, skin erythema, and weight loss. The addition of nonirradiated spleen cells or non-UVB-irradiated T-cell subsets (both CD4 and CD8 positive) to the otherwise UVB-irradiated donor inoculum consistently resulted in acute GVHD. In contrast, UVB irradiation of these cells resulted in full engraftment without acute GVHD. Mixed lymphocyte culture (MLC) assays confirmed responsiveness by BM transplanted hosts to third party stimulators while coculture assays failed to show any in vitro suppressor activity in the host. We conclude that UVB acts on both the T-lymphocyte and antigen presenting cell (APC) subsets to prevent acute GVHD. We also propose a model to explain tolerance based on clonal anergy produced by modified antigen presentation by UVB-irradiated APC's or by a modified response to processed antigen.

Animals↗
PubMed1996

Localization of endocrine pancreatic islets.

Transplantation of whole pancreas or pancreatic islets remains a promising approach to treatment of diabetes mellitus. Because at present there is no efficient method for in vivo early diagnosis of pancreatic islet rejection or for disorders of pancreatic endocrine function, we examined if dithizone (DTZ) and a synthetic iodo-derivative of DTZ (I-DTZ) can be used as a potential radioactive marker for monitoring viable transplanted pancreatic islets. Human pancreatic islets harvested from multiorgan donors were tested ex vivo after intraductal injection of DTZ solution for islet staining. Lewis rats were used in the in vivo experiments for localizing pancreatic islets in situ after intravenous injection of various concentrations of DTZ or I-DTZ. Fresh rat islets were transplanted into streptozotocin-induced diabetic recipients, either underneath the kidney capsule or intraperitoneally. Intravenous DTZ or I-DTZ was then used for macroscopic and microscopic identification of viable transplanted islets. These studies indicate that DTZ and I-DTZ solutions specifically stain pancreatic islets in vivo after intravenous injection without damage to their endocrine function as assessed by plasma insulin and glucose levels. Human islets stain red in in vitro studies similar to the DTZ (I-DTZ) effect in rats. We conclude that DTZ and I-DTZ are effective in the in vivo and in vitro identification of pancreatic islets and may have potential clinical application in the detection of pancreatic islet tumors (insulinomas) and in the diagnosis of rejection of pancreatic organ allografts or islets.

Animals↗
PubMed1996

In vitro evaluation of neonatal human immunity against the pig.

The critical shortage of organ donors has greatly limited the number of clinical allotransplantations. This is particularly true for neonatal patients, for whom xenotransplantation could provide an alternative therapeutic option to allotransplantation. The role of neonatal infant immunity in xenotransplantation is not, however, clearly understood. We examined both the proliferative responses of human neonatal lymphocytes to pig aortic endothelial cells and serum levels of neonatal natural antipig xenoantibody. Neonatal human lymphocytes and serum were isolated from umbilical cord blood. Adult human lymphocytes and serum were used as controls. A one-way xenogeneic mixed lymphocyte-endothelial cell reaction was performed, and lymphocyte proliferation was measured by tritiated thymidine uptake. Neonatal human lymphocytes recognized and proliferated in response to pig aortic endothelial cells (mean 63,926 +/- 26,054 counts per minute). The level of xenogeneic mixed lymphocyte-endothelial cell reaction of neonatal lymphocytes was significantly lower (p < 0.004) than that of adult human lymphocytes (mean 122,444 +/- 33,132 counts per minute). An enzyme-linked immunosorbent assay was performed to determine the binding of natural immunoglobulin M and G antibodies to pig endothelial cells. Whole-cell enzyme-linked immunosorbent assay demonstrated neonatal human serum to contain very low binding levels of natural antipig immunoglobulin M xenoantibody compared with adult serum. Like adult serum, neonatal human serum contained natural antipig immunoglobulin G xenoantibody. Neonatal serum was not cytotoxic to pig endothelial cells, suggesting that immunoglobulin G was not the predominant xenoreactive antibody. To assess whether neonatal pig endothelial cells also expressed xenoantigens, adult and neonatal cultured pig endothelial cells were examined by enzyme-linked immunosorbent assay with adult human serum. Adult human natural immunoglobulin M xenoantibody recognized not only adult pig endothelial cell xenoantigens but also neonatal pig endothelial cell xenoantigens. The binding levels of adult natural antipig immunoglobulin M xenoantibodies to adult and neonatal pig endothelial cells were similar, suggesting that neonatal pig aortic endothelial cells express xenoantigens. The findings of low binding levels of cytotoxic antipig immunoglobulin M xenoantibody and low levels of lymphocyte xenoreactivity to pig endothelial cells in human neonates suggests that pig organs may eventually be a suitable source of xenografts for human neonates.

Adult↗
PubMed1995

Prevention of graft-versus-host disease and the induction of transplant tolerance by low-dose UV-B irradiation of BM cells combined with cyclosporine immunosuppression.

GVHD is prevented and stable chimerism is induced in the rat BMT model by 700 J/m2 but not 100-500 J/m2 UV-B irradiation of allogeneic BM cells. Paradoxically, CsA which prevents GVHD in clinical BMT causes an aggressive autoimmune disease termed syngeneic GVHD in irradiated syngeneic BMT recipients after its withdrawal. Recently, we have shown that while 500-700 J/m2 UV-B irradiation of syngeneic BM cells combined with a 30-day course of CsA recipient immunosuppression impairs hemopoiesis due to lack of hemopoietic factors, a low dose of 100-300 J/m2 UV-B is effective in preventing CsA-induced autoimmune disease without endangering BM engraftment. This study extends these findings to the P-to-F1 hybrid and fully allogeneic rat BMT models and examines the effectiveness of low-dose UV-B irradiation of BM cells combined with a short course of CsA treatment in the prevention of GVHD and induction of transplant tolerance. Lethally gamma-irradiated (10.5 Gy) LBNF1 recipients of naive or UV-B irradiated (100-700 J/m2) BMT were treated with CsA (12.5 mg/kg/day) for 30 consecutive days after BMT. All lethally irradiated LBNF1 that did not receive BMT died in < 16 days, while animals transplanted with UV-B (700 J/m2) BMT survived > 1 year without GVHD. In contrast, all recipients of naive BMT died of lethal GVHD in < 50 days. Similarly, all recipients of naive BMT that received a 30-day course of CsA therapy developed severe GVHD with 60% mortality after cessation of CsA therapy. CsA-treated recipients of BMT irradiated with 700 J/m2 died between 12 and 25 days from failure of hemopoiesis. In contrast, CsA-treated recipients of 100-200 J/m2 UV-B irradiated BMT showed full BM engraftment without GVHD after cessation of CsA and survived > 1 year. These results were reproducible in the fully allogeneic UV-B BMT model. To test for donor-specific tolerance, the animals challenged 100 days after BMT with cardiac allografts accepted permanently (> 100 days) Lewis but not BN (non-BMT parental donor) cardiac allografts. Our results confirm that 700 J/m2 UV-B irradiation of BM cells combined with CsA recipient immunosuppression impairs the recovery capacity of stem cells while the use of lower UV-B (100-200 J/m2) is effective in preventing CsA-induced autoimmune disease without endangering BM engraftment and leads to induction of transplant tolerance.

Animals↗
PubMed1995

Transplantation tolerance to rat cardiac and islet allografts by posttransplant intrathymic inoculation of soluble alloantigens.

The search for strategies for induction of specific tolerance in adult animals that will avoid long-term host immunosuppression with its complications has led to the deliberate introduction of alloantigens (Ag) into the adult thymus. However, pretransplant intrathymic (IT) inoculation of alloantigens (Ag), which has consistently induced tolerance to vascularized and neovascularized allografts in adult rodents, has limited future clinical application. To overcome the practical limitations of pretreatment, we have examined in the Lewis-to-WF combination the effect on graft survival of either simultaneous or posttransplant IT inoculation of soluble Ag obtained from 3M KCl extracts of donor T cells in transiently rabbit antirat lymphocyte serum (ALS) immunosuppressed recipients. While IT injection of 2.0 mg soluble Ag alone on day of cardiac transplantation caused acute graft rejection, IT inoculation of 2.0 mg Ag combined with 1 ml ALS transient immunosuppression of the recipient on day 0 led to long-term graft survival (> 250 days) in 5/6 recipients. Similarly, IT injection of soluble Ag on posttransplant day 3 or day 7 combined with 1 ml ALS on day 0 relative to allografting resulted in permanent graft survival in all recipients. In contrast, intravenous injection of soluble Ag combined with ALS immunosuppression on day 0 led to acute graft rejection that paralleled the rejection seen in ALS treated controls. Third-party Brown Norway (BN) hearts were acutely rejected in similarly prepared recipients of IT-Ag, thus confirming donor specificity. The long-term unresponsive Wistar-Furth (WF) recipients challenged 100 days after cardiac transplantation with a second-set graft specifically and permanently (> 100 days) accepted the second-set donor cardiac allografts, thus demonstrating donor-specific tolerance. In similar experiments, IT inoculation of 2 mg soluble Ag combined with transient ALS immunosuppression resulted in donor-specific unresponsiveness to islets in the same rat combination of Lewis-to-WF. Our findings suggest that this new strategy of immunologic manipulation of the adult thymus offers a safe, effective, and reproducible method of inducing tolerance that may have therapeutic application in cadaveric organ transplantation.

Animals↗
PubMed1995

Tolerance induction to cardiac allografts by simultaneous or sequential intrathymic inoculation of disparate alloantigens.

Recent studies show that the adult immune system can be manipulated to accept allografts by the intrathymic (IT) inoculation of donor alloantigens (Ag). To make this model clinically applicable to cadaveric transplants, we have examined the effect of simultaneous or sequential IT injection of two disparate Ags on graft survival. In initial experiments, Wistar Furth (WF) rats received IT injections of a single or an admixture of 2 x 10(7) Lewis T cells and 2 x 10(7) BN T cells 7 days prior to cardiac transplantation. Untreated WF recipients acutely rejected single Lewis, BN, and ACI heart allografts, respectively, at times equivalent to rejection of double hearts while IT injection of single or double 2 x 10(7) Lewis and 2 x 10(7) BN T cells on day -7 also led to acute graft rejection. As expected, IT injection of donor-type resting T cells combined with 1 ml ALS recipient immunosuppression on day -7 led to donor-specific Lewis or BN permanent graft survival (> 200 days). The long-term unresponsive WF recipients challenged 100 days after cardiac transplantation with 2nd-set grafts specifically and permanently accepted 2nd-set donor cardiac allografts. IT injection of an admixture of 2 x 10(7) Lewis and 2 x 10(7) BN T-cells combined with 1 ml ALS on day -7 resulted in 100% permanent double (Lewis and BN) allograft survivals (> 150 days). Similar treatment led to acute rejection of third-party (ACI) grafts while the simultaneously transplanted Lewis hearts survived indefinitely (> 150 days). In the second group of experiments, unresponsive recipients of single (Lewis or BN) cardiac allografts were given IT inoculation of a second Ag in a sequential fashion 30 or 100 days after primary heart transplant. Unresponsive WF recipients of Lewis grafts accepted permanently (> 100 days) second BN grafts that were transplanted 30 or 100 days after primary Lewis graft and 7 days after IT injection of BN T-cells and 1 ml ALS. Similarly, unresponsive WF recipients of BN grafts accepted second Lewis grafts after IT injection of Lewis T cells combined with ALS, 30 or 100 days after primary BN grafts. To define the mechanism of peripheral tolerance in this model, we have shown that adoptive transfer of unseparated spleen cells from unresponsive recipients induces prolonged double (Lewis and BN) graft survivals (> 60 days) but not ACI grafts in sublethally irradiated (400 rads) syngeneic (WF) recipients, thus suggesting that maintenance of tolerance is, in part, dependent on suppressor/regulatory cell network.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Effects of ultraviolet-B irradiation on human LAK and NK cytotoxic activity.

In vitro ultraviolet-B (UVB) irradiation of murine and rodent bone marrow cells prevents GVHD without compromising engraftment while inducing tolerance to donor-type allografts. In anticipation of clinical trials of UVB-modified bone marrow grafts, we studied the in vitro effects of UVB irradiation (50-300 J/m2) on human natural killer and lymphokine activated killer cells since both types of cells influence the development of GVHD and graft-versus-tumor effect. Interleukin-2-activated and untreated human lymphocytes were used as effectors in a 51Cr release cytotoxic assay against various tumor cell lines as targets. NK-mediated lysis of K562 targets was decreased by UVB irradiation of the effector cells in a dose-dependent manner. FACS analysis of CD16+ and CD56+ cells 24 hr after UVB exposure showed a UVB-dose-dependent decrease in the number of cells expressing these surface markers. UVB irradiation of lymphocytes prior to activation with high-dose IL-2 resulted in a range of 20- to 89-fold decrease in LAK precursors as measured by limiting dilution analysis using the LAK-sensitive cell line HL60. In contrast, the LAK activity of lymphocytes that had been stimulated in vitro with high-dose IL-2 prior to UVB irradiation was preserved when assayed immediately after UVB modulation; however, there was a significant decrease in lytic activity (with most samples tested) when the assay was performed 24 hr after UVB exposure. It appears that the lymphocyte response to UVB modification is dose dependent, with some cell types displaying higher sensitivity to UVB irradiation than others. These findings suggest that prevention of GVHD by UVB is due, in part, to inhibition of NK activity, and may offer a new strategy to augment the graft versus leukemia effect of UVB-modified bone marrow grafts in clinical transplantation.

Bone Marrow Transplantation↗
PubMed1995

Induction of peripheral tolerance by intrathymic inoculation of soluble alloantigens: evidence for the role of host antigen-presenting cells and suppressor cell mechanism.

Intrathymic (IT) inoculation of soluble alloantigens (Ag) obtained from 3 M KCl extracts of resting T-cells induces donor-specific tolerance to cardiac allografts and islet allografts. This study examined the cellular basis of induction of transplantation tolerance by IT injection of soluble Ag. Our results show that while IT inoculation of 2 mg soluble donor Ag on Day -7 relative to Lewis islet transplantation induced specific unresponsiveness to islet allografts (> 200 days) in naive diabetic recipients, IT inoculation of 2 mg soluble Ag on the same day as islet transplantation did not prolong islet allograft survival in the same Lewis-to-WF rat combination. To define the role of donor APCs in intrathymic tolerance, we showed that IT injection of an admixture of 1 x 10(4) donor DC and 2 mg soluble Ag caused acute islet graft rejection. In contrast, addition of 1 x 10(4) recipient-type DC to the IT inoculum did not prevent long-term graft survival. This finding suggests that while the presence of donor APCs in the inoculum does not appear necessary for IT-alloantigen to induce peripheral tolerance, presentation of the soluble Ag in the thymus is dependent on host APCs. This conclusion is supported by our in vitro MLR experiments which showed that in vivo WF-Ag-primed Lewis T-cells proliferated specifically to WF-soluble Ag and that the response was enhanced 14-fold by the addition of responder-type DC. Addition of anti-Lewis MHC class II mAb specifically blocked the alloresponse, thus suggesting that in vivo Ag-primed T-cells are capable of recognizing and proliferating in response to allopeptides presented by responder APCs. We also showed that adoptive transfer of syngeneic naive T-cells into unresponsive recipients failed to break tolerance to long-term surviving islet allografts. This finding suggests that tolerance in this model is not due to a lack of T help. On the other hand, the adoptive transfer of spleen cells, but not sera, from the unresponsive WF recipients bearing long-term (> 120 days) functioning Lewis islets resulted in prolonged survival of donor-type but not third-party islet allografts in secondary syngeneic hosts. Our data suggest that the tolerogenic effect of IT inoculation of soluble Ag is dependent on the indirect pathway of Ag presentation and clonal deletion of alloreactive T-cells in the thymus, while suppressor/regulatory mechanism may be involved in the maintenance of peripheral tolerance.

Animals↗
PubMed1995

Donor-specific unresponsiveness to murine cardiac allografts induced by intrathymic-soluble alloantigens is dependent on alternate pathway of antigen presentation.

This study extends the finding that intrathymic (IT) inoculation of uv-B irradiated donor spleen cells (SC) or soluble alloantigens (Ag) induces peripheral tolerance to organ allografts in the rat to the murine cardiac allograft model. In our initial experiment, we showed that IT inoculation of uv-B irradiated SC combined with transient immunosuppression of the recipient with either sublethal TBI or ALS on Day -7 led to donor-specific, long-term cardiac allograft survival (> 300 days) in the completely mismatched A/J-to-C57BL/6 mice combination. To test our hypothesis that peripheral tolerance induced by IT injection of donor Ag is dependent on presentation of the foreign MHC molecule by thymic APC to T cell precursors, we examined the effect of IT injection of donor APC-free-soluble Ag inoculum obtained from 3 MKCl extracts of purified MHC class I resting T cells on cardiac allograft survival in the A/J-to-C3H mice combination. The results showed that IT injection of the optimal dose of 500 micrograms soluble Ag combined with 0.5 ml ALS on Day -7 led to donor-specific permanent graft survival (> 200 days). This finding could not be reproduced by intravenous administration of soluble Ag, thus confirming the privileged position of the thymus in tolerance induction. To further define the role of host APC in allorecognition, we studied the presentation of soluble Ag by responder APC in MLR. The results showed that primed T cells obtained from A/J skin graft-sensitized C3H T cells specifically developed alloreactivity to A/J-soluble Ag in MLR.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Prevention of cyclosporine-induced syngeneic graft-versus-host disease in bone marrow transplantation by UV-B irradiated bone marrow cells.

UV-B irradiation of allogeneic rat bone marrow cells (BMC) transplanted into lethally gamma-irradiated recipients prevents GVHD and induces stable complete hematopoietic chimerism. Cyclosporine (CsA), an effective immunosuppressive agent, causes an autoimmune syndrome termed syngeneic GVHD in syngeneic radiation chimeras following discontinuation of CsA. To understand the in vivo interactions of CsA with UV-B modulated syngeneic bone marrow transplant (BMT), as this is essential before clinical use, we studied the effects of CsA therapy in recipients of UV-B irradiated donor BMT in the rat model. Lethally irradiated (10.5 Gy) Lewis recipients of naive or UV-B irradiated syngeneic BMT (admixture of 10(8) BMC and 5 x 10(6) spleen cells) were treated with CsA (i.m. 12.5 mg/kg/day) for 30 consecutive days after BMT. The results show that all irradiated Lewis recipients of syngeneic BMT modulated with 700 J/m2 UV-B were hematologically fully reconstituted in 25-35 days and survived their normal life span. In contrast, all lethally irradiated recipients of untreated BMT that received CsA for 30 days developed lethal acute syngeneic GVHD 7-12 days after CsA withdrawal. Of interest is the finding that while higher doses of UV-B (500-700 J/m2) irradiation of BMC prior to transplantation into CsA-treated animals prevented hemopoietic reconstitution, lower doses (100-300 J/m2) allowed for hemopoietic recovery and, in addition, prevented the development of syngeneic GVHD following the discontinuation of CsA. The development of syngeneic GVHD was dependent on the presence of the thymus and did not occur in thymectomized recipients.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗