Modification of Graft-versus-Host Disease with Con A and Preimmunization 1

Abstract

Graft-versus-host disease (GVHD) is one of the major obstacles to the routine successful transfer of bone marrow cells between histoincompatible individuals. Allogeneic bone marrow contains mature T-lympho-cytes that upon engraftment are able to recognize and react against the foreign transplantation antigens of the host, producing a syndrome of acute or delayed morbidity and mortality as a result of a graft-versus-host immune reaction (1, 2). This has limited the use of bone marrow grafts in man to exchanges between individuals closely related antigenically; however, even in those cases where there is apparent HL-A compatibility, some degree of GVHD is common (3). It is clear, therefore, that the scope and efficacy of bone marrow therapy would be greatly enhanced if a way could be found to eliminate from bone marrow preparations those mature lymphocytes that produce GVHD without adversely affecting the erythroid, myeloid, and lymphoid stem cells.

Previous work (4) has shown that when allogeneic murine bone marrow and spleen cell preparations are incubated with concanavalin A (Con A) at concentrations sufficient to kill or inhibit mature T cells and then are injected into irradiated hosts, the majority of stem cells survive to protect the recipients against the effects of the radiation, and GVHD either is prevented entirely or the incidence is greatly reduced. Overall, 84% of 140 mice given Con A treated cells were alive and healthy 100 days after irradiation whereas none of the mice given untreated cells survived (mean survival time, 16.2 days). While these results were encouraging, nonspecific toxic effects limited the concentration of Con A that could be used to 300 μ/ml or less and thus precluded the elimination of all T cells from heavily contaminated marrow specimens without risking severe damage to vital stem cell populations. In an attempt to increase the survival of recipients of marrow preparations heavily contaminated with mature T-lymphocytes, mice were immunized with sheep RBC (SRBC) 3 days before radiation in an effort to activate suppressor T cells (5); after irradiation they were injected with large numbers of Con A treated allogeneic marrow and spleen cells. The results of these experiments suggest that the activation of host suppressor T cells may be a valuable adjunct in the prevention of GVHD induced by foreign T-lymphocytes.