Alloimmune Or Autoimmunelike Manifestations Following alloBMT

GVHD is a systemic disease caused by T cells in donor bone marrow attacking antigen-presenting cells and tissues of host origin, often causing acute morbidity and mortality during the first few weeks post-BMT. Chronic GVHD may develop several months after BMT. Therefore, GVHD is in fact a purely iatrogenic "autoimmune-like" disease that may affect almost every tissue, with skin, gastrointestinal tract and liver being the primary candidates. Indeed, chronic active hepatitis, vasculitis, autoimmune neuropathies and autoimmune thrombocytopenia, anemia and leukopenia are rather frequent complications. Chronic GVHD may also mimic lichen planus in the mucous membranes, ophthalmoxerostomia (Sjogren's sicca syndrome) and focal or systemic progressive sclerosis (scleroderma), chronic active hepatitis and SLE, to name just a few of the clinical syndromes that may result from acute and chronic GVHD. Interestingly, some of the symptoms are alloimmune (e.g., chronic active hepatitis) whereas others, as will be detailed below, are autoimmune (e.g., reactivity against hematopoietic cells of donor origin in the course of GVHD). In most centers, the incidence of GVHD is still very high, despite the use of various drugs to prevent GVHD, with acute GVHD observed in 50-70% of patients, with severe or occasionally fatal outcome in approximately 20-30% and 10% of the recipients, respectively. Once severe GVHD occurs, there is no effective cure.

One possible method to control GVHD while retaining the benefits of donor T cells may include T-cell-depletion at the time of alloBMT, to prevent immediate GVHD while avoiding post-transplant immunosuppressive agents, followed by late infusions of donor blood lymphocytes given in graded increments while controlling for GVHD [27]. Administration of graded increments of DLI as has been used for prevention of relapse in high-risk patients [30],

Several new approaches are currently in the pipelines for down-regulation of donor antihost responses by selective elimination of effector T-cell subsets, regulation of antihost reactivity by veto of alloreactive T cells or using genetically engineered T cells that harbor a suicide gene that can be used to limit their life span [44], In addition, we have recently developed a new regimen for alloBMT based on the use of nonmyeloablative stem-cell transplantation (NST) [29]. Such a modality, which focuses on elimination of host lymphocytes to prevent rejection, rather on myeloablative therapy, may provide a safer protocol for patients with autoimmune diseases that may be candidates for alloBMT.

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