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- Qi, Zhongquan, et al.
(författare)
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Single dose anti-CD4 monoclonal antibody for induction of tolerance to cardiac allograft in high- and low-responder rat strain combinations
- 1997
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Ingår i: Transplant Immunology. - 0966-3274. ; 5:3, s. 204-211
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Tidskriftsartikel (refereegranskat)abstract
- Repeated administration of monoclonal antibodies (mAb) directed against the CD4 lymphocyte receptor may induce specific, long-lasting unresponsiveness to fully MHC-mismatched cardiac allografts in rats without additional immunosuppression. We assessed the effect of a single dose of murine anti-rat depleting anti-CD4 mAb (OX-38) on allograft survival in high- and low-responder rat strain combinations. Isogenic strains of DA (RT1(av1)), PVG (RT1(c)), AUG (RT1(c)), and WF (RT1(u)) rats were used. Recipients in antibody treated groups were given one dose of 5 mg/kg OX-38 mAb on the day of transplant, a dose which was shown to effectively deplete (or block) circulating CD4+ T cells. Other groups were treated for 10 days with cyclosporin A (CsA) and/or Linomide, a novel immunomodulator, which is the first compound able to fully eliminate the effect of CsA in the rat cardiac allograft model. The DA strain was identified as a low-responder to the allogeneic haplotype RT1(c) (PVG or AUG), but not to RT1(u) (WF), and developed true tolerance following RT1(c) grafting and OX-38 or low-dose CsA (5 mg/kg) induction, as verified by the response to retransplantation of a graft from the same donor strain or a third-party challenge. PVG recipients of DA grafts were characterized by high response and only modest (OX-38; median 9.5 days) or moderate (CsA; 23.5 days) prolongation of graft survival. Contrasting graft survival results were obtained in the low-responder combination, either very early rejection (at 10 days) or permanent graft survival (> 100 days). Linomide challenge affected CsA treatment in the high-responder combination but not tolerance induction in the low-responder combination, or the effect of OX-38. It was concluded that in rat heart transplantation a single-dose anti-CD4 mAb therapy may induce permanent donor-specific unresponsiveness in a low-responder strain combination, and that anti-CD4 mAb seems to be unique among immunosuppressive agents while being resistent to challenge by Linomide.
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- Östraat, Öyvind
(författare)
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Experimental modulation and suppression of anti-allograft immune response
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Abstract The objective of this investigation was to characterise the immunomodulatory or immunosuppressive effects of single drug treatment and the potential synergistic or additive effects of combined treatment with the focus on ciprofloxacin, thalidomide, mycophenolate mofetil, azathioprine, cyclophosphamide or leflunomide added to cyclosporin A (CyA). A rat cardiac transplant model was used to study graft survival and the influence on lymphocytes was evaluated by in vitro tests. Ciprofloxacin stimulated rat lymphocyte proliferation and IL-2 production in vitro and reduced the inhibitory effect of CyA at low concentrations. In the transplant model, however, graft survival was enhanced and further prolonged by combined treatment with ciprofloxacin and CyA. Addition of thalidomide to cultures of human or rat lymphocytes was not associated with any inhibitory effects. On the contrary, after incubation with metabolised thalidomide, the IL-2 production was significantly increased. However, thalidomide reduced the rat CD4 /CD8 T cell ratio and was demonstrated to prolong graft survival. The immunomodulatory drug linomide may induce rejection in the transplant model despite CyA treatment and this was used to test additive or synergistic effects of combined therapy with CyA and another drug. Thalidomide and CyA, as dual treatment, overcame the challenge of linomide. Mycophenolate mofetil and cyclophosphamide prolonged graft survival as sole treatment but azathioprine did not. However, all three drugs were demonstrated to enhance the immunosuppressive effect of CyA when studied in the linomide model. Leflunomide was found to induce graft unresponsiveness as sole treatment in a low responder rat strain combination. The criteria for the linomide model were fulfilled only in a high responder rat strain combination and now the effect of leflunomide was reduced only when given in a low dose regimen. An additive effect was demonstrated after combined leflunomide and CyA treatment in this model.
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- Östraat, Öyvind, et al.
(författare)
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Mycophenolate mofetil, azathioprine and cyclophosphamide enhanced efficacy combined with cyclosporine in rat cardiac transplantation
- 1997
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Ingår i: Scandinavian Journal of Immunology. - 1365-3083. ; 45:4, s. 343-348
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Tidskriftsartikel (refereegranskat)abstract
- Anti-proliferative drugs have been used for immunosuppression since the introduction of clinical transplantation. Most transplant centres include azathioprine (Aza) and cyclosporine (CyA) in their standard regimens, despite several controlled studies having failed to confirm the benefit of this combination. Aza is still. the most commonly used anti-proliferative drug, although no major differences in immunosuppressive or toxic effects have been shown between Aza and cyclophosphamide (Cph). Cph as an adjunct to CyA has never been tested in a randomized study. Recently, mycophenolate mofetil (MMF) has been developed as the most selective inhibitor of T- and B-cell proliferation and promoted as an adjunct to CyA treatment, In the present study, the additive or synergistic effects of these three anti-proliferative agents in combined treatment with CyA have been investigated using a rat cardiac transplantation model in which the immunomodulator linomide (Lin) was included as a potentiator of rejection. As single drug treatment, CyA, Cph and MMF, but not Aza, exerted a beneficial effect on graft survival. This prolongation of graft survival was abrogated when any one drug was administered together with Lin. The addition of MMF, Aza or Cph to CyA plus Lin treatment improved the graft survival significantly, thus demonstrating each of the anti-proliferative drugs to exert additive or synergistic effects in conjunction with cyclosporine. MMF seemed to be the most effective and least toxic of the drugs tested.
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