Demonstration of active tolerance in maintenance of established islet of Langerhans allografts.

Abstract

Streptozotocin-induced diabetes in mice can be reversed by transplantation of islets of Langerhans from histoincompatible mice if the islets are treated with anti-Ia-serum and complement before transplantation. Here we show that anti-Iatreated islets most likely induce tolerance in the recipient animals. Daily injections of recipient-specific anti-I-J-serum (beginning 80 or more days after transplantation) and small numbers of donor splenocytes caused the prompt rejection of the islets in half of the animals; neither anti-I-J-serum nor donor splenocytes alone were effective. It is likely that rejection of established allografts after this treatment is the result of abolition of the activity of allograftspecific suppressor cells. Graft acceptance may also be prolonged if grafts depleted of passenger lymphocytes activate suppressor cells in the recipient, thus leading to a state of tolerance. Cellular (4,5) and humoral (6, 7) immunity have been shown to be regulated by antigen-specific suppressor T lymphocytes. Such suppressor cells, which express I-J determinants (8), probably inhibit both T helper cells and B cells stimulated by an antigenic challenge and lead to antigen-specific nonresponsiveness. Suppressor cells have been shown to be important in tumor immunity (9) and in unresponsiveness to tissue allografts in mice rendered tolerant neonatally (10). Treatment of mice with specific anti-I-J sera increases primary antibody responses (11) and suppresses tumor growth (12), presumably by eliminating I-J-bearing suppressor T cells. In the present investigation anti-I-J serum and donor splenocyte injections were used to determine iftolerance was present in the mice bearing successful islet allografts. The publication costs ofthis article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact.

Allotransplantation of Islet Endocrine Aggregates

“…Induction of established grafts. Rats with long-term (>60 days) islet or neoislet grafts were challenged with donor strain splenocytes to determine the mechanism of graft acceptance (13,14). Donor strain spleens (Lewis) were minced with scissors, and single-cell suspensions were obtained by pressing them through a fine nylon mesh and then treating them withTris-buffered ammonium chloride to lyse erythrocytes.…”

Experimental immuno‐alteration

“…In our early investigations on established islet allografts in rats, we had found some evidence of induction of specific tolerance in these animals [11]. In studies on mice that established islet allografts, following pretreatment of the islets with Ia antibody and complement, we found that repeated injections of anti-I-J antisera in conjunction with a single injection of only 10 4 donor spleen cells would induce rejection of established islet allografts in mice [12]. In control animals with established islet allografts of similar duration, >10 7 donor spleen cells were required to induce rejection.…”

Theory and practice of immunoregulation by tissue treatment prior to transplantation

“…Lymphocytes from "tolerant" animals respond normally to donor alloantigens in vitro [53,54]. More recently, Faustman et al [55] suggested that such unresponsiveness may be due to the action of suppressor cells; the role of suppressor cells in allograft tolerance has been reviewed elsewhere [56].…”