Transplant Immunology 9 (2002) 289–294 0966-3274/02/$ - see front matter  2002 Elsevier Science B.V. All rights reserved. PII:S0966-3274 Ž 02 . 00041-2 Islet xenograft rejection in absence of CD8 T cells does not require q either interferon-g or interleukin-5 Laurent Crenier *, Alain Le Moine , Robert Kiss , Willy J. Malaisse , Michel Goldman a,b, b c d b Department of Endocrinology, Hopital Erasme, Universite Libre de Bruxelles, 808 route de Lennik, B-1070 Brussels, Belgium a ˆ ´ Laboratory of Experimental Immunology, Universite Libre de Bruxelles, 808 route de Lennik, B-1070 Brussels, Belgium b ´ Laboratory of Histopathology, Universite Libre de Bruxelles, 808 route de Lennik, B-1070 Brussels, Belgium c ´ Laboratory of Experimental Medicine, Universite Libre de Bruxelles, 808 route de Lennik, B-1070 Brussels, Belgium d ´ Abstract We recently demonstrated that interleukin-5 and eosinophils mediate rejection of skin allografts when CD8 T cell-dependent q and Th1-type CD4 T cell-dependent pathways are not functional. The purpose of this study was to determine whether a similar q mechanism might be operative during rejection of rat islet xenografts in mice. First, we observed that eosinophils indeed infiltrate rejected islet grafts together with CD4 and CD8 T cells. CD8 T cell depletion significantly enhanced graft survival and a q q q further prolongation of islet function was obtained in combination with interferon-g neutralization. However, islet rejection characterized by prominent eosinophil and macrophage infiltration still occurred in this setting. Although eosinophil infiltrates were dramatically reduced in interleukin-5 deficient mice, the ability of these animals to reject islet xenografts under CD8 T q cell depletion and interferon-g neutralization was similar to that of wild-type mice. We conclude that in absence of CD8 T cells q and interferon-g, macrophages, but not eosinophils, mediate rejection of rat-to-mouse islet xenografts.  2002 Elsevier Science B.V. All rights reserved. Keywords: Eosinophils; Interleukin-5; Islet; Macrophage; Pancreas; Xenograft 1. Introduction Transplantation of pancreatic islet xenografts is thought to have clinical potential in the near future, because xenogeneic cells might escape the early hyper- acute rejection encountered with vascularized xenografts w1,2x. However, experimental models established that islet xenografts undergo delayed rejection by cellular mechanisms that are different from those involved in classical alloimmune responses w3–6x. Both CD4 and q CD8 T cells were shown to contribute to the rejection q of concordant islet xenotransplants, but the effector mechanisms leading to graft destruction remain largely unknown w5–8x. In contrast to allogeneic islet rejection, where a dominant Th1-type response was documented, cytokine gene expression in rejected islet xenografts revealed accumulation of both Th1-type (IL-2, IFN-g) and Th2-type (IL-4, IL-5, IL-10) mediators, often with *Corresponding author. Tel.: q32-2-555-3407; fax: q32-2-555- 6755. E-mail address: lcrenier@ulb.ac.be (L. Crenier). evidence for Th2 dominance and eosinophil infiltrates w4,9–11x. Although rejection of fetal pig islets in mice occurred, even when eosinophil infiltration was prevent- ed by IL-5 deficiency w12x, this study did not exclude that eosinophils become key effectors when other mech- anisms of cytotoxicity are impaired, as we recently observed in a model of skin allograft rejection w13x. 2. Objective The primary objective of this study was therefore to determine the role of eosinophils in the rejection of rat islet xenografts in mice when classical pathways of graft rejection are inhibited. For this purpose, we first estab- lished the presence of eosinophils in rejected xenografts. We then inhibited CD8 T cell-dependent and IFN-g- q dependent pathways of graft rejection and investigated in this setting the magnitude of the eosinophil infiltrates and the effect of IL-5 deficiency on the survival of functional islet grafts.