SEVERE GRAFT-VERSUS-HOST DISEASE IN SCID MICE IS ASSOCIATED WITH A DECREASE OF SELECTIVE DONOR CELL TCR V-BETA SPECIFICITIES AND INCREASED EXPRESSION OF IFN-GAMMA AND IL-4

Differences in T-cell selection and severity of graft-versus-host (GVH ) disease were observed in immunodeficient C.B-17 SCID (SCID) mice aft er injection of allogeneic T lymphocytes from CBA/J or C57B1/6 (B6) mi ce. Infiltrating donor cells were analysed in bone marrow (BM), liver and spleen of newborn recipients and 5 days post-engraftment the numbe r of B6 cells significantly exceeded that of CBA/J cells in these orga ns. At that time, cells in BM of B6 and CBA/J injected recipients were augmented in intracellular IL-4, IL-10, and TNF-alpha, whereas only c ells in B6 treated BM were increased in IFN-gamma, and both treated gr oups of mice had upregulated endogenous MHC class I and class II expre ssion in the three organs. Already on day 5, and more pronounced day 1 0, B6 treated SCIDs had a relative decrease of four different TCR-V be ta specificities among donor cells, whereas CBA/J injected mice had an abnormal expansion of V beta 14(+) donor T cells 10 days post injecti on. At the same time, the total cell contents of BM and spleen of B6 i njected mice were substantially decreased, and this was paralleled by signs of severe GVHD; whereas SCIDs treated with CBA/J exhibited much milder symptoms. Moreover, adult SCID mice injected with V beta 2, 4, 8 and 14 depleted B6 T cells showed an increased percentage of infiltr ating donor cells and an enhanced decrease in BM cell content compared to SCIDs treated with total B6 T cell repertoire. In vitro, the V bet a 2, 4, 8 and 14 depleted population was more responsive to SCID splee n stimulators. Thus, a disturbed immunoregulation among donor T cells, caused by multiple changes in the TCR repertoire, may be responsible for inducing the severe GVHD.