engleski

Graft-versus-leukemia effect with or without graft-versus-host disease?

Attempts to treat leukemia by whole-body X-irradiation and infusion of bone marrow cells from healthy volunteers date fifty years ago. The aim was to eradicate neoplastic cells and restore normal hematopoiesis. At that time, combined chemotherapy for neoplastic disease as we know it today was in its early stages, remission rates were low and the long-term survival exceptional. Transplantation of normal bone marrow offered a hope for cure, but initial results were unsatisfactory. The reasons are now understandable: patients were in advanced stages of the disease, tissue typing for selection of a compatible donor was not yet available, and efficient post-transplant immunosuppression was not yet developed. Poor engraftment, transplant related toxicity and severe graft-versus-host reactions were common. The graft-versus-host reaction, or so-called secondary disease, was pronounced "the stumbling block in the treatment of leukemia by whole-body irradiation and transfusion of allogeneic hematopoietic cells". Nevertheless, its potential to eliminate leukemia cells resisting the exposure to high doses of X-rays was recognized. That "graft-versus-leukemia reaction" was clearly demonstrated in experimental models (mice with transplaned leukemia) in the 1960's but its true clinical significance was confirmed and accepted twenty years later. In the meantime, efforts in clinical bone marrow transplantation were directed toward complete prevention, obviation or at least mitigation of the graft-versus-host reaction. Recipients and donors of the bone marrow were matched as closely as possible by means of tissue typing in the same way as in solid organ transplantation, lymphoid cells capable of mounting an immune attack against the host were eliminated from the graft by means of centrifugation, antibodies, absorption columns etc, and immunosuppressive chemotherapy by methotrexate, cyclophosphamide and other drugs was given in the posttransplantation period. Conditioning regimens for the transplantation included aggressive chemotherapy aimed at maximal elimination of neoplastic cells. Autologous bone marrow from which the neoplastic cells were purged by in vitro manipulation were used instead of the allogeneic grafts. These measures resulted in bone marrow transplantation becoming a reasonably safe clinical procedure with acceptable treatment toxicity, reliable engraftment and reduced incidence of severe graft-versus-host reactions. It became evident, however, that successfully transplanted patients free of graft-versus-host reaction are prone to leukemia relapse. On the other hand, relapses occured less frequently in patients who did develop chronic graft-versus-host disease. Those observations renewed the interest in graft-versus-leukemia reaction as a therapeutic tool. Since 1980, the number of papers dealing with possibility of harnessing graft-versus-host reaction for leukemia cure has steadily increased – from four in 1981-5 to two hundred in 1996-2000 and again in 2001-4. Research efforts were directed toward dissection of the graft-versus-leukemia reaction from the graft-versus-host disease. Various ideas and approaches have been explored, from manipulations of the graft in vitro to interventions and treatments of the recipient in the post-transplantation period. Myeloablative conditioning for the bone marrow grafting was replaced by less aggressive regimens resulting in mixed chimerism and mutual tolerance of host and donor cells, which permitted delayed infusion of donor lymphocytes at appropriate times after the grafting so as to elicit anti-leukemia reaction as deemed appropriate. Hematopoietic stem cells from peripheral blood and neonatal cord blood cells were used for the transplantation instead of bone marrow cells. Predominant views were that graft-versus-host and graft-versus-leukemia reactions were mediated by different classes, subclasses or clones of immunocompetent cells from the graft (CD4, CD8, NK, LAK, Th1, Th2, Tc1, Tc2), were aimed towards discrete targets (leukemia-specific antigens, minor histocompatibility antigens), and were driven by distinct cytokines (IL-2, IL-12, IFN, TNF). Elimination of incriminated cell class, subclass or clone from the graft, or alternatively their enrichment or enhancement before or after the grafting, was expected to dissociate the 'useful' graft-versus-leukemia action from unwanted graft-versus-host damage. It was also presumed that graft-versus-host and graft-versus-leukemia reactions ran different time courses and were separable in time rather than in specificity. Timely termination of graft's activity against the host was pursued by rendering the lymphocytes to be grafted sensitive to gancyclovir or another agent by means of transfection so that the reactive cells could be eliminated as as deemed appropriate. Dissection of the graft-versus-leukemia effect from the graft-versus-host reaction was indeed feasible in mouse models or with human cells in vitro, but so far a clear-cut distinction between the two was not achieved in clinical situations. Notorious dictum of Paracelsus Bombastus von Hohenheim "What makes a man ill also cures him" must not be forgotten.

presađivanje koštane srži; reakcija presatka protiv primatelja; reakcija presatka protiv leukemije

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