NEUTRALIZING IL-12 DURING INDUCTION OF MURINE ACUTE GRAFT-VERSUS-HOSTDISEASE POLARIZES THE CYTOKINE PROFILE TOWARD A TH2-TYPE ALLOIMMUNE RESPONSE AND CONFERS LONG-TERM PROTECTION FROM DISEASE

Injection of parental spleen cells into BDF1 mice results in a graft-v s-host disease (GVHD), the nature of which is critically dependent on the parental haplotype, E6 --> BDF1 mice develop a Th1-mediated immuno suppressive lethal GVHD, whereas DBA/2 --> BDF1 mice develop a Th2-dep endent chronic GVHD, characterized by autoantibody production and glom erulonephritis. In this study we show that neutralizing endogenous IL- 12 for a brief period during the initiation of acute GVHD in B6 --> BD F1 mice not only confers long term protection from the acute disease, but also permits full repopulation of the recipient with donor B6 lymp hocytes. Antibody-treated animals showed normal T cell proliferation i n response to Con A stimulation and remained healthy throughout the st udy, Splenocytes from such mice showed reduced in vitro production of IFN-gamma and enhanced production of IL-5 and IL-10, suggesting a perm anent switch from a Th1 to a Th2 cytokine response, comparable to that associated with chronic GVHD in DBA/2 --> BDF1 mice, In contrast to D BA/2 --> EDF1 mice, however, anti-IL-12-treated B6 --> BDF1 mice displ ayed only mild B cell hyper-responsiveness, as evidenced by a modest i ncrease in serum IgG acid IgE levels and moderate levels of anti-dsDNA Abs, Importantly, however, anti-IL-12-treated B6 --> BDF1 mice showed no evidence of immune complex-mediated glomerulonephritis. These resu lts demonstrate that neutralizing IL-12 is an effective means of preve nting acute GVHD and does not result in the development of chronic GVH D, which might otherwise limit its application.