Graft-Versus-Host Disease the Development of Acute Versus Chronic Molecule/Inducible Costimulator Antibody on Lymphocyte- Immunomodulatory Opposing Effects of Anti-Activation-Inducible

The functional role of inducible costimulator (ICOS)-mediated costimulation was examined in an in vivo model of alloantigen-driven Th1 or Th2 cytokine responses, the parent-into-F 1 model of acute or chronic graft-vs-host disease (GVHD), respectively. When the Ab speciﬁc for mouse ICOS was injected into chronic GVHD-induced mice, activation of B cells, production of autoantibody, and development of glomerulonephritis were strongly suppressed. In contrast, the same treatment enhanced donor T cell chimerism and host B cell depletion in acute GVHD induced host mice. Blocking of B7-CD28 interaction by injection of anti-B7-1 and anti-B7-2 Abs inhibited both acute and chronic GVHD. These observations clearly indicate that the costimulatory signal mediated by CD28 caused the initial allorecognition resulting in the clonal expansion of alloreactive T cells, whereas the costimulatory signal mediated by ICOS played a critical role in the functional differentiation and manifestation of alloreactive T cells. Furthermore, treatment with anti-ICOS Ab selectively suppresses Th2-dominant autoimmune disease. The Journal of Immunology, 2001, 167: 5741–5748. AILIM/ICOS with Ab strongly enhanced the production of the cytokines IL-4, IFN- (cid:1) and IL-10, but not IL-2 (29, 33). To examine the role of AILIM/ICOS during in vivo development of Th1 and Th2 response, we tested the effect of anti-AILIM/ICOS mAb in the parent-into-F 1 model of graft-vs-host disease (GVHD). The advan-tage of this murine system is that, depending on the parental strains injected, the same host develops either an anti-host cell-mediated, Th1 cytokine-driven disease (acute GVHD) or an autoantibody-mediated, systemic lupus erythematosus-like Th2 cytokine-driven disease (chronic GVHD) in response to the same Ag (39, 40). Our results indicate that administration of anti-AILIM/ICOS mAb selectively attenuates Th2-driven chronic GVHD, but Th1-driven acute GVHD is accelerated by the same treatment. Because blockade of CD28 signal with CTLA4-Ig or anti-B7 Ab completely abrogated both acute and chronic GVHD, our ﬁndings clearly indicated that CD28 and ICOS play a distinct role in T dependent immune responses. Furthermore, the manipulation of ICOS-mediated costimulation can be a therapeu-tic strategy for Th2-mediated immune disease. Our results indicate that the blockade of CD28/B7 interaction by CTLA4-Ig or anti-B7-1 plus anti-B7-2 mAb treatment aborted both acute and chronic GVHD, whereas blockade of ICOS-B7 h interaction by anti-AILIM mAb treatment selectively inhibited development of chronic GVHD. These results suggest that CD28-mediated T cell costimulation is critically required for the initiation of alloreactivity of T cells, including expansion, presumably with autocrine IL-2, cytokine production, and up-regulation of ICOS and other cell surface receptors. In contrast, ICOS-B7 h interaction may be dispensable for primary T cell response to alloantigens but play an important role for the differentiation of immune responses.