Induction of Donor‐Specific Allograft Tolerance by Short‐Term Treatment with LF15‐0195 After Transplantation. Evidence for a Direct Effect on T‐Cell Differentiation

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Abstract
A 20‐day treatment with LF15–0195, a deoxyspergualine analog, induced long‐term heart allograft survival in the rat without signs of chronic rejection. LF15–0195‐treated recipients did not develop an anti‐donor alloantibody response. Analysis of graft‐infiltrating cells, IL10, TNFα, IFNγ mRNA and iNOS protein expression in allografts, 5 days after transplantation, showed that they were markedly decreased in allografts from LF15–0195‐treated recipients compared with allografts from untreated recipients. Surprisingly, spleen T cells from LF15–0195 recipients, 5 days after grafting, were able to proliferate strongly in vitro, when stimulated with donor cells, but had reduced mRNA expression for IFNγ compared with spleen T cells from untreated graft recipients. Furthermore, when T cells from naive animals were stimulated in vitro, using anti‐CD3 and anti‐CD28, LF15–0195 also increased T‐cell proliferation in a dose‐dependent fashion; however, these cells expressed less of the Th1‐related cytokines, IFNγ and IL2, compared with untreated cells, suggesting that LF15–0195 could act on T‐cell differentiation. In conclusion, we show here that a short‐term treatment with LF15–0195 induced long‐term allograft tolerance, decreasing the in situ anti‐donor response, and we illustrate evidence for the development of regulatory mechanisms.