Académie royale de Médecine de Belgique

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Michel Goldman

(Séance du 28 octobre 2000)

EFFECTORS MECHANISMS OF ALLOGRAFT REJECTION : A ROLE FOR TH2-TYPE RESPONSES       

par M. GOLDMAN, membre titulaire, et MM. A. Lemoine, W. Braun, V. Flamand et D. Abramowicz (Laboratory of Experimental Immunology – ULB), coll.

T cells expressing CD4 molecules on their membrane (CD4+ T cells) play an essential role in the orchestration of allograft rejection. Indeed, CD4+ T cells are required for the induction of cell-mediated immune responses involving activated macrophages or cytotoxic CD8+ T cells as well as for the activation of B cells and their differentiation into antibody-producing cells.  CD4+ T cells clones generated in vitro produce distinct sets of cytokines : the TH1 clones preferentially synthesize interferon-gamma (IFN-у) which is responsible for the activation of macrophages, whereas the TH2 clones preferentially secrete interleukin (IL)-4, IL-5, IL-6, IL-9, IL-10 and IL-13 which collectively induce growth, differentiation and activation of B cells, eosinophils and mast cells.

Acute cellular rejection is usually considered as a TH1-type process involving IFN-у as a Key mediator through its stimulatory action on the expression of major histocompatibility molecules and the activation of macrophages.  On the other hand, it has been proposed that the non-aggressive CD4+ T cells which are commonly observed in accepted allografts might belong to the TH2 subset.  This concept is challenged by several recent studies.  Indeed, we developed several models in which IL-5 secretion by TH2 cells results in rejection of allografts.  First, we studied the rejection of skin grafts from bm12 mice as donors in Fas-L-deficient gld C57/BL/6 mice as recipients, a model of major histocompatibility complex class II incompatibility in which the recipient is unable to mount anti-donor cytolytic responses.  Massive eosinophil infiltrates were found in rejected allografts and their critical role in the rejection process was demonstrated by the prolongation in allograft survival upon OL-5 neutralization.  The involvement of eosinophils was also demonstrated in acute rejection of heart allografts in the setting of CD8+ T cell depletion. In parallel, we found that a short course of anti-CD3 monoclonal antibody inwild-type C57BL/6 mice, grafted with bm12 skin resulted in chronic skin allograft rejection, characterized by intense dermal fibrosis, obliterative intimal vasculopathy and leukocytic infiltrates rich in eosinophils.  Because these changes occurred in the absence of alloreactive antibodies, we examined the contribution of cytokines in their pathogenesis.  Chronically rejected grafts showed a marked accumulation of both IL-4 and IL-5 MRNA.  The use of IL-4- or IL-5- deficient mice as recipients allowed to established the critical role of TH2-type cytokines in this model of chronic rejection.

We conclude that TH2-type responses can result in both acute and chronic rejection of allografts.  This alternate effector mechanism becomes critical when cytotoxic and THI-type responses are deficient.            

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