ANTIGEN-PRESENTING CELLS (APC) OF MICE WITH CHRONIC GRAFT-VERSUS-HOSTDISEASE (GVHD) CAUSE EXCESSIVE ACTIVATION-INDUCED DEATH OF T-HELPER CELLS

Both experimental and clinical forms of chronic GVHD have unique immun ological features. The affected animals/individuals suffer from autoim mune disorders such as systemic lupus erythematosus (SLE), and yet the y are unable to mount a self MHC-restricted T cell response to foreign antigens. Pathogenesis of the latter phenomenon was investigated in a n experimental model of chronic GVHD. Chronic GVHD was induced in 8-10 -week-old (B6 x C3H)F-1 mice by tail vein injection of 5 x 10(7) splee n cells of C3H parental strain. The recipients, when tested 3 months l ater, were unable to mount a T helper (Th) cell response to a randomly selected immunogen, a vaccine of 10(8) killed Mycobacterium vaccae. T he animals showed evidence of generalized lymphoid hyperplasia, as ind icated by GVH index >1.34, and also revealed autoantibodies against er ythrocytes and dsDNA, indicating establishment of chronic GVHD. Howeve r, mice with chronic GVHD of only 3 weeks duration were able to mount the Th cell response to M. vaccae. Three consecutive immunizations of these mice at 1-week intervals, with the same immunogen, resulted in t he mice becoming non-responsive to the antigen. All the three response s tested, namely the DTH, lymphoproliferation and the antibody respons es, were adversely affected. The non-responsiveness induced was antige n-specific. Mice receiving two immunizations with M. vaccae responded normally to Salmonella enteritidis. Pulse treatment with cyclosporin A 0.5 mg/mouse by the i.p. route, on days 0, 1, 2, 3 and 4 at the time of immunization with M. vaccae on day 1, prevented emergence of non-re sponsiveness. Based on this evidence, it was concluded that repeated a ctivation of T cells of mice with chronic GVHD induces non-responsiven ess. Extent of clonal loss due to activation-induced cell death (AICD) caused by i.p. injection with a superantigen Staphylococcal enterotox in B (SEB) was investigated in F-1 mice with chronic GVHD. I.p. inject ion of 25 mu g/mouse of SEB induced loss of SEB responding clones in b oth normal F-1 mice and those having chronic GVHD; however, the extent of loss was much greater in the latter. In vitro antigen-specific pro liferation of primed splenic T cells of normal F-1 mice was observed t o be quite poor when antigen was presented by APC of mice with chronic GVHD of 3 weeks duration. Proliferation profiles of T cells of normal F-1 mice, in response to stimulation with concanavalin A (Con A) or S EB, were studied, using as APC irradiated spleen cells of normal F-1 m ice or of F-1 mice with chronic GVHD of 3 weeks duration. With Con A a nd APC of normal Fl mice, peak proliferation was observed at 48 h, whi ch remained at the same level up to 72 h and declined thereafter, poss ibly due to AICD. With SEB and the normal APC, proliferation progressi vely peaked at 72 h and declined thereafter. With APC of mice with chr onic GVHD, the 48 h proliferative responses of both Con A and SEB were comparable to those caused by APC of normal F-1 mice; however, therea fter the responses declined steeply, suggesting greater AICD. Based on these results, it was concluded that APC of mice with chronic GVHD ar e functionally altered to induce greater AICD.