Immunological tolerance induced by liver grafting in the rat: splenic macrophages and T cells mediate distinct phases of immunosuppressive activity

Abstract

SUMMARYIn the rat combination DA into PVG, liver grafts are not rejected but induce donor-specific transplantation tolerance. We have examined the immunosuppressive properties of spleen cells from PVG recipients of DA liver grafts at various times post-grafting. The results indicate the development of two phases of cell-mediated suppressor activity, which appear to be mediated by separate spleen cell populations. Mitomycin-C-treated spleen cells taken from animals between 5 and 28 days postgrafting were able to suppress rat mixed lymphocyte reactions (MLRs). These 'early' suppressor cells were glass adherent and absent from populations purified by passage through nylon wool or GIO Sephadex columns. Suppression of MLR by purified glass adherent cells was not specific for either stimulator or responder haplotypes and was blocked by indomethacin. Nylon wool purified T cells were not suppressive at this time. Spleen cell suppressor activity declined to background levels after 35 days post-grafting. However, spleen cells from long-term surviving liver graft recipients (20 weeks or more) were again able to suppress MLR; the 'late' suppressor cells were nylon wool non-adherent and suppression was specific for the donor (DA) MHC type. We conclude that liver grafting in this combination generates early and late phases of suppression among spleen cells, that the early phase is produced by macrophages and mediated by prostaglandins and that the late phase is dependent on allospecific suppressor T cells.

The Liver: A Special Case in Transplantation Tolerance

“…Early studies in rats suggested that tolerance to liver grafts involves immune suppression, as splenocytes of recipients were able to suppress an allo-MLR. 186 These experiments showed that there were two spleen cell populations involved in the suppressive activity, an early-acting population enriched in macrophages that was nonspecific and mediated by prostaglandins and a late-acting population developing after 35 days that was specific and depended on T cells. Subsequent studies confirmed the presence of suppressor T cells after liver transplantation.…”

The CD8 T‐cell response during tolerance induction in liver transplantation

“…This process was donor-specific and provided long-lasting suppression. 123 Other studies have confirmed that splenocytes isolated at day 60 after liver transplantation were more effective at providing allograft protection compared with those isolated at day 30. 124 Early studies have also suggested that donor T cells, presumably Tregs, may contribute to the maintenance of allograft tolerance.…”

“…63 Interestingly, most studies suggest that T regs able to efficiently suppress the function of alloreactive T cells require several weeks to develop. One of the earliest studies by Kamada and co-workers 123 on this topic identified two distinct phases of suppression in the spleen mediated by different cells. An early first immunosuppressive phase occurred between 5 and 28 days after liver transplantation.…”

Monocyte-Derived Suppressor Cells in Transplantation

“…Macrophages obtained from prednisone plus azathioprine treated human kidney transplant patients mediated cell cytotoxicity, as measured by release of 3 H-thymidine labeled target cells in vitro. Later in 1991, Kamada and colleagues reported two phases of cell-mediated suppressor activity, involving macrophages and regulatory T cells, respectively, in an experimental rat liver transplant model [ 14 ]. Early after transplantation (4–34 days), adherent suppressor macrophages present in the spleen of tolerant recipients mediated the in vitro inhibitory function measured by suppression of mixed leukocyte reactions, while late after transplantation (20 weeks), non-adherent suppressor T cells were responsible for the suppressive function of recipient splenic cells.…”

“…Early after transplantation (4–34 days), adherent suppressor macrophages present in the spleen of tolerant recipients mediated the in vitro inhibitory function measured by suppression of mixed leukocyte reactions, while late after transplantation (20 weeks), non-adherent suppressor T cells were responsible for the suppressive function of recipient splenic cells. Moreover, macrophage-mediated suppression was dependent on prostaglandins, since indomethacin inhibited their suppressive function [ 14 ]. These results suggested that non-specific suppressor macrophages develop in the spleens of tolerant liver transplant recipients.…”