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

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, TNFa, IFNg 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 IFNg 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, IFNg 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.

Implication of Matrix Metalloproteinase 7 and the Noncanonical Wingless-Type Signaling Pathway in a Model of Kidney Allograft Tolerance Induced by the Administration of Anti-Donor Class II Antibodies

“…The time-dependent up-regulation of MMP7 transcripts in tolerated kidneys (no expression on day 0 and increasing expression on day 25 to day 100 after transplantation compared with syngeneic or acutely rejected grafts) suggests that this molecule may play a role in maintaining tolerance. Interestingly, this role appears to be specific to the anti-donor class II model of kidney transplantation, as no up-regulation of MMP7 was observed in other models of kidney transplant tolerance in the same strain combination (anti-CD28 tolerance induction protocol (41); data not shown) or in models of heart tolerance or chronic rejection (LF015-095 and DST protocols) (9,21,42). We have already shown in the laboratory that different mechanisms may operate following different tolerance induction protocols, even in the same genetic LEW.1W to LEW.1A background (8).…”

“…The model used was that of heart allotransplantation from LEW.1W donors to MHC-mismatched LEW.1A recipients receiving either a donor-specific blood transfusion (DST) 7 and 14 days before transplantation (2) or a 20-day course of the deoxyspergualin analog LF015-095 (21). At day 100 posttransplantation, the grafts of DST-treated animals show clear-cut histological signs of chronic humoral rejection (chronic transplant vasculopathy) (9), whereas those of LF015-095-treated animals do not and are thus tolerated (21,22). Analyses were performed on DST-treated (n ϭ 3) and LF015-095-treated recipients (n ϭ 3) at day 100 posttransplantation.…”

“…We therefore compared MMP7 expression in tolerated kidneys to that observed in long-surviving heart grafts (day 100 posttransplantation) transplanted in the same allogeneic strain combination (LEW.1W to LEW.1A). To induce heart allograft tolerance, we used different protocols: DST 7 and 14 days before transplantation (grafts showing clear histological signs of chronic rejection) (9) or a 20-day course of the deoxyspergualin analog LF015-095 (grafts showing no signs of rejection; i.e., tolerated) (21). The results clearly show an absence of MMP7 expression in heart grafts from both DST-treated (chronic rejection) and LF015-095-treated (tolerated) recipients at this time (Fig.…”

The C-Type Lectin-Like Receptor CLEC-1, Expressed by Myeloid Cells and Endothelial Cells, Is Up-Regulated by Immunoregulatory Mediators and Moderates T Cell Activation

“…LEW.1W (RT1u) or LEW.1A (RT1a) rats served as heart donors, and LEW.1A rats served as recipients. For allograft tolerance models, LF15-0195 (20 days) (Fournier Laboratories) or antidonor class II Abs were administered to recipients as previously described (12,13). Chronic allograft rejections were induced by two donor blood transfusions (donor-specific transfusion (DST)) before transplantation or by CD40-Ig administration as previously described (8,14).…”

Induction of transplantation tolerance in non-human primate preclinical models

“…Major differences in the patterns of MHC expression combined with a far less complex immune system conspire to make rodent tolerance models considerably more permissive than those of higher animals and man. As a consequence, the transplant literature contains many examples of successful tolerance induction regimens that have been developed in rodents ( Jirsch et al 1974;Angelisova et al 1983;Gutstein et al 1986;Chavin et al 1993;Chikaraishi et al 1995;Yang et al 1995;Bashuda et al 1996;Brandt et al 1997;Lehmann et al 1997;Alexander et al 1998;Hayamizu et al 1998;Lindner & Zantl 1998;Gao et al 1999;Zhang et al 2000;Gregori et al 2001;Chiffoleau et al 2002;Adorini et al 2003;Guo et al 2003;Jin et al 2003;Nanji et al 2003) while only a few have been successfully applied to non-human primates (NHPs) or the clinic with any degree of success. Accordingly, prospective protocols developed in rodent models normally require vetting in a large animal model in order to better appreciate their therapeutic potential for use in human trials.…”