Graft vs autoimmunity following allogeneic non-myeloablative blood stem cell transplantation in a patient with chronic myelogenous leukemia and severe systemic psoriasis and psoriatic polyarthritis

Objective. No specific therapy exists for autoimmune diseases caused by sel f-reactive lymphocytes. As shown in experimental animals, which led to pilo t clinical studies, elimination of self-reactive lymphocytes can be accompl ished with high-dose chemoradiotherapy, followed by autologous stem cell tr ansplantation, by re-establishment of unresponsiveness to self antigens of newly generated lymphocytes, due to a mechanism of central clonal deletion. We hypothesized that self-reactive lymphocytes causing autoimmune disease may be successfully eliminated by highly immunosuppressive Set not necessar ily myeloablative conditioning in conjunction with allogeneic blood stem ce ll transplantation, since immunocompetent alloreactive lymphocytes of donor origin can effectively eliminate residual host-type hematopoietic cells, s elf-reactive lymphocytes included, by a mechanism that resembles graft-vs-l eukemia (GVL) effects. The present report is an attempt to confirm the exis tence of graft-vs-autoimmunity (GVA) effects in parallel with amplification of the alloreactive potential of donor lymphocytes following allogeneic no n-myeloablative stem cell transplantation (NST). Methods. We identified a patient with severe psoriatic arthritis who also h ad Philadelphia (bcr/abl) positive chronic myelogenous leukemia and therefo re was fully eligible for NST. Both diseases responded initially to non-mye loablative conditioning involving fludarabine 30 mg/m(2) X 6, anti-T-lympho cyte globulin 10 mg/kg X 4, and busulfan 4 mg/kg X 2. Results. The initial NST procedure was uneventful and resulted in eliminati on of all signs of autoimmunity (psoriasis and arthritis). Recurrence of po lyarthritis and exacerbation of psoriasis were observed in parallel with a significant increase in the proportion of male (host) DNA, slid 5% of the m itoses were bcr/abl positive, indicating an increase in the clone of CML. B oth bcr/abl-positive cells identified by RT-PCR and psoriatic arthritis wer e successfully eliminated following discontinuation of anti-GVHD prophylaxi s with cyclosporine ri (CSA), which resulted in activation of the alloreact ive potential of donor T cells, accompanied by graft-vs-host disease (GVHD) , suggesting the existence of GVA effects. RT-PCR for bcr/abl remains consi stently negative for nearly 3 years, and all DNA remains donor type. Conclusions. The response of autoimmune disease manifestations to GVA effec ts in parallel with elimination of all host-derived hematopoietic cells sup ports our working hypothesis that autoimmune diseases caused by self-reacti ve lymphocytes may be effectively treated by elimination of alloreactive se lf-reactive lymphocytes following induction of host-vs-graft tolerance, in analogy with replacement of malignant or genetically abnormal host cells fo llowing DLI. It is therefore suggested that intentional GVA effects mag be inducible by DLI following a conventional or preferably safer non-myeloabla tive regimen in recipients with life-threatening autoimmune diseases resist ant to conventional modalities. Adoptive immunotherapy of autoimmunity may thus involve a two-step procedure: first, inducing host-vs-graft and graft- vs-host transplantation tolerance through a transient stage of mixed chimer ism; second, inducing controlled GVA effects, initially by discontinuation of CSA and then, if indicated, by late outpatient DLI to eradicate residual hematopoietic cells of host origin. (C) 2000 International Society for Exp erimental Hematology. Published by Elsevier Science Inc.