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Graft-Versus-Leukemia

Human alloantigen-specific anergic cells induced by a combination of CTLA4-Ig and CsA maintain anti-leukemia and anti-viral cytotoxic responses

Abstract

The success of allogeneic hematopoietic stem cell transplantation from HLA-disparate donors depends on the development of new strategies for graft-versus-host disease prevention able to target specifically donor antihost alloreactivity, while preserving GVL and antiviral immune surveillance. Recent experimental and clinical work has shown the feasibility of an approach based on induction of anergy to host alloantigens through blockade of B7/CD28 costimulatory signal in donor T cells, but data on the impact of this strategy on the recovery of the immune system are still lacking. We devised an ex vivo method for induction of host alloantigen-specific unresponsiveness based on treatment with the B7/CD28 blocking agent CTLA4-Ig associated with CsA. We then proceeded to assess the maintenance of an effective immune response towards viral pathogens and tumor cells after CTLA4-Ig/CsA treatment, by measuring the frequency of CTL precursors directed against CMV- and EBV-infected targets, and against autologous leukemic blasts. We demonstrated that (1) CTLA4-Ig and CsA can act synergistically in inducing a state of unresponsiveness to alloantigens; (2) the number of leukemia-reactive, EBV-specific and CMV-specific CTLp is not impaired by CTLA4-Ig/CsA treatment. Our data provide the first direct in vitro evidence that it is possible to preserve antiviral and antileukemia effector cells after blockade of CD28/B7 interaction during MLR. Bone Marrow Transplantation (2001) 27, 1263–1273.

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Acknowledgements

This work was supported in part by grants from the Associazione Italiana Ricerca sul Cancro (AIRC) to FL and to RM by grants No.261RFM96/01, 390RFM97/01, and RCR98 from IRCCS Policlinico S Matteo to FL and RM, and by a grant from MURST (Ministero dell'Università e della Ricerca Scientifica) to FL. We thank Dr Malcolm Brenner for valuable discussion and critical reading of this manuscript. We also wish to thank Massimo Labirio for excellent technical assistance, Elena Percivalle for viral preparations, and Carlo Carbognani for valuable hardware and software computer assistance.

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Comoli, P., Locatelli, F., Moretta, A. et al. Human alloantigen-specific anergic cells induced by a combination of CTLA4-Ig and CsA maintain anti-leukemia and anti-viral cytotoxic responses. Bone Marrow Transplant 27, 1263–1273 (2001). https://doi.org/10.1038/sj.bmt.1703063

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