Quantitative studies on tissue transplantation immunity. IX.* Induction of tolerance with antilymphocytic serum

Abstract

Antilymphocytic serum (ALS) belongs to the class of immunosuppressive agents that will abet the induction of transplantation tolerance. Acute treatment with ALS followed by the intravenous injection of (CBA $\times $ A) lymphoid cells will allow CBA mice to accept A-strain grafts for periods of the order of months. The timing of the tolerance-conferring injections of lymphoid cells is critical: premature injections merely sensitize (section 3$\cdot $1). Up to a point, repeated injections are preferable to single injections (section 3$\cdot $1). The duration of tolerance varies directly with the size of the tolerance-conferring dose (section 3$\cdot $2). The intravenous route of injection is superior to the subcutaneous and the intraperitoneal (section 3$\cdot $3). Induced tolerance is immunologically specific (section 3$\cdot $4, section 4$\cdot $3). Whole blood and thymocytes are as effective as splenic or lymph-node cells in conferring tolerance, but syngeneic (CBA) lymphoid cells are ineffective. Cells from ALS-treated A-strain donors are somewhat less effective than cells from normal untreated hybrid donors. Lymphoid cells from ALS-treated donors do not cause runt disease. Single pulses of cell-free antigen have no detectable action, but repeated injections secure some measure of tolerance (section 3$\cdot $5). Tolerance may be established in strongly presensitized mice, though less readily than in normal mice (section 3$\cdot $6). Although ALS itself discriminates very little between 'strong' and 'weak' histocompatibility differences, the induction of tolerance with ALS obeys the conventional rule that it is more difficult in proportion to the antigenic disparity between donor and host (section 3$\cdot $7). The action of ALS in inducing tolerance is strongly potentiated by doses of irradiation or of cyclophosphamide which would be negligibly ineffective in themselves (section 3$\cdot $8). Evidence was sought that a skin graft may secure tolerance on its own behalf in ALS-treated mice, but the results were equivocal (section 3$\cdot $9). The induction of tolerance in respect of transplantation immunity extends also to humoral antibody formation (section 4$\cdot $1). Tolerance is accompanied by a chimerism that slowly fades, though it can be temporarily reinstated by renewed lymphoid cell injections (section 4$\cdot $2). Cells from the central lymphoid organs of mice tolerant of A-strain antigens retain the power to react against C57 antigens in the Simonsen test (section 4$\cdot $3). It is argued that differences between conventional and ALS-induced tolerance can be explained in terms of cellular population dynamics. Lymphoid cells injected into ALS-treated animals do not proliferate to occupy spaces emptied by the massive cellular depletion that accompanies (for example) irradiation, and their descendants are at a selective disadvantage vis-a-vis the regenerating lymphoid system of the host. The state of tolerance is therefore relatively short-lived (section 5). Two phenomena nevertheless remain unexplained: the fact that grafts transplanted before a course of ALS begins live longer than grafts transplanted after such a course has ended (section 3$\cdot $9), and the fact that an intensive course of treatment with ALS is more effective in presensitized than in virgin mice (section 3$\cdot $6).