Trends in Immunology
OpinionA role for eosinophils in transplant rejection
Section snippets
Acute allograft rejection induced by Th2-type CD4+ T cells
The first data suggesting a role for Th2-type CD4+ T cells in the induction of allograft rejection were generated in murine models, where Th2 polarization of the alloimmune response was achieved either by CD8+ T cell depletion or interleukin (IL)-12 antagonism in vivo 2, 3. Indeed, acute rejection in CD8? T-cell-depleted mice was associated with the local production of IL-4 and IL-5 together with eosinophil infiltration 2. More direct evidence for Th2-cell-mediated rejection was provided by
The IL-5–eosinophil pathway of acute allograft rejection
IL-5 is a central mediator of eosinophilic inflammation 8, 9, regulating the differentiation, growth and activation of eosinophils as well as their extravasation into tissues. Because of the selective effect of IL-5 on the eosinophil lineage, the availability of mice genetically deficient in IL-5 and the ability to neutralize IL-5 in vivo, the role of eosinophils in experimental, allergic or parasitic diseases can be determined 10, 11. A similar approach was followed to investigate the role of
IL-4 and IL-9 cooperate with IL-5 in the pathogenesis of transplant eosinophilia
In allergic lung inflammation tissue, eosinophilia was shown to depend on the cooperation of IL-5 with IL-4 and IL-13 (Ref. 16). IL-4 is also involved in eosinophilic graft rejection as IL-4 neutralization enabled the long-term survival of B6bm 12 skin grafts in B6 mice (A. Lemoine et al., unpublished). IL-4 and IL-13 promote eosinophil extravasation, at least in part, by upregulating the expression on endothelial cells of vascular cell adhesion molecule (VCAM)-1, a major adhesion molecule for
CD8+ T cells prevent eosinophilic graft rejection
As shown in Table 1, most models of eosinophilic graft rejection are characterized by a lack of CD8+ T-cell activity, either because donor–recipient disparity does not involve MHC class I antigens or because of CD8+ T-cell depletion before transplantation. Recent data indicate that, in the absence of CD8+ T-cell regulation, the default response of alloreactive CD4+ T cells is a sustained production of Th2-type cytokines, whatever the genetic background 26. We recently observed that, even after
Chronic allograft rejection: a Th2-type pathology?
In clinical transplantation the chronic form of rejection is responsible for most long-term graft failures. It represents a major challenge for transplant biologists as it is barely affected by current immunosuppressive therapies. The hallmarks of chronic rejection are parenchymal fibrosis and obliterative vasculopathy. Although both antibody-mediated and cell-mediated pathways of chronic rejection have been identified 29, its pathogenesis remains poorly understood. We recently developed a
Concluding remarks
Experimental observations strongly suggest that eosinophils contribute to both acute and chronic graft damage in the context of a Th2-type alloimmune response. These findings might be of clinical relevance as eosinophils are often observed in human transplants during rejection episodes 33, 34, 35, 36. Thus, new agents targeting the IL-5–eosinophil pathway, such as anti-IL-5 monoclonal antibodies or CCR3 antagonists, might be of therapeutic value, not only in allergic disorders but also in organ
Acknowledgements
Studies presented in this paper were supported by a Pole d'attraction interuniversitaire from the Belgian federal government, an Action de recherche concertée of the Communauté française de Belgique, the Fonds de la recherche scientifique médicale (Belgium), and the Biotech program of the European Commission. We thank M. Pretolani for her contribution to the demonstration of the role of IL-5 in graft rejection and R. Kiss for histological studies.
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