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

The success of allogeneic hematopoietic stem cell transplantation from HLA- disparate donors depends on the development of new strategies for graft-ver sus-host disease prevention able to target specifically donor antihost allo reactivity, while preserving GVL and antiviral immune surveillance. Recent experimental and clinical work has shown the feasibility of an approach bas ed 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 strat egy on the recovery of the immune system are still Lacking. We devised an e x vivo method for induction of host alloantigen-specific unresponsiveness b ased on treatment with the B7/CD28 blocking agent CTLA4-Ig associated with CsA. We then proceeded to assess the maintenance of an effective immune res ponse 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 un responsiveness to alloantigens; (2) the number of leukemia-reactive, EBV-sp ecific 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 pre serve antiviral and antileukemia effector cells after blockade of CD28/B7 i nteraction during MLR.