PMID- 10907647
OWN - NLM
STAT- MEDLINE
DCOM- 20000802
LR  - 20191025
IS  - 0301-472X (Print)
IS  - 0301-472X (Linking)
VI  - 28
IP  - 7
DP  - 2000 Jul
TI  - 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.
PG  - 853-7
AB  - OBJECTIVE: No specific therapy exists for autoimmune diseases caused by 
      self-reactive lymphocytes. As shown in experimental animals, which led to pilot 
      clinical studies, elimination of self-reactive lymphocytes can be accomplished 
      with high-dose chemoradiotherapy, followed by autologous stem cell 
      transplantation, 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 yet not necessarily 
      myeloablative conditioning in conjunction with allogeneic blood stem cell 
      transplantation, since immunocompetent alloreactive lymphocytes of donor origin 
      can effectively eliminate residual host-type hematopoietic cells, self-reactive 
      lymphocytes included, by a mechanism that resembles graft-vs-leukemia (GVL) 
      effects. The present report is an attempt to confirm the existence of 
      graft-vs-autoimmunity (GVA) effects in parallel with amplification of the 
      alloreactive potential of donor lymphocytes following allogeneic 
      non-myeloablative stem cell transplantation (NST). METHODS: We identified a 
      patient with severe psoriatic arthritis who also had Philadelphia (bcr/abl) 
      positive chronic myelogenous leukemia and therefore was fully eligible for NST. 
      Both diseases responded initially to non-myeloablative conditioning involving 
      fludarabine 30 mg/m2 x 6, anti-T-lymphocyte globulin 10 mg/kg X 4, and busulfan 4 
      mg/kg x 2. RESULTS: The initial NST procedure was uneventful and resulted in 
      elimination of all signs of autoimmunity (psoriasis and arthritis). Recurrence of 
      polyarthritis and exacerbation of psoriasis were observed in parallel with a 
      significant increase in the proportion of male (host) DNA, and 5% of the mitoses 
      were bcr/abl positive, indicating an increase in the clone of CML. Both 
      bcr/abl-positive cells identified by RT-PCR and psoriatic arthritis were 
      successfully eliminated following discontinuation of anti-GVHD prophylaxis with 
      cyclosporine A (CSA), which resulted in activation of the alloreactive potential 
      of donor T cells, accompanied by graft-vs-host disease (GVHD), suggesting the 
      existence of GVA effects. RT-PCR for bcr/abl remains consistently negative for 
      nearly 3 years, and all DNA remains donor type. CONCLUSIONS: The response of 
      autoimmune disease manifestations to GVA effects in parallel with elimination of 
      all host-derived hematopoietic cells supports our working hypothesis that 
      autoimmune diseases caused by self-reactive lymphocytes may be effectively 
      treated by elimination of alloreactive self-reactive lymphocytes following 
      induction of host-vs-graft tolerance, in analogy with replacement of malignant or 
      genetically abnormal host cells following DLI. It is therefore suggested that 
      intentional GVA effects may be inducible by DLI following a conventional or 
      preferably safer non-myeloablative regimen in recipients with life-threatening 
      autoimmune diseases resistant 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 chimerism; 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.
FAU - Slavin, S
AU  - Slavin S
AD  - The Department of Bone Marrow Transplantation, The Cancer Immunotherapy & 
      Immunobiology Research Center, Hadassah University Hospital, Jerusalem, Israel. 
      slavin@cc.huji.ac.il
FAU - Nagler, A
AU  - Nagler A
FAU - Varadi, G
AU  - Varadi G
FAU - Or, R
AU  - Or R
LA  - eng
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - Exp Hematol
JT  - Experimental hematology
JID - 0402313
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Immunosuppressive Agents)
RN  - FA2DM6879K (Vidarabine)
RN  - G1LN9045DK (Busulfan)
RN  - P2K93U8740 (fludarabine)
SB  - IM
MH  - Adult
MH  - Antineoplastic Agents/therapeutic use
MH  - Arthritis, Psoriatic/*complications/immunology
MH  - *Autoimmunity
MH  - Busulfan/therapeutic use
MH  - Graft vs Host Disease/complications/immunology
MH  - Graft vs Leukemia Effect/immunology
MH  - Hematopoiesis
MH  - *Hematopoietic Stem Cell Transplantation
MH  - Humans
MH  - Immunosuppressive Agents/therapeutic use
MH  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*complications/*immunology
MH  - Lymphocytes/immunology
MH  - Male
MH  - Psoriasis/*complications/immunology
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Vidarabine/analogs & derivatives/therapeutic use
EDAT- 2000/07/25 11:00
MHDA- 2000/08/06 11:00
CRDT- 2000/07/25 11:00
PHST- 2000/07/25 11:00 [pubmed]
PHST- 2000/08/06 11:00 [medline]
PHST- 2000/07/25 11:00 [entrez]
AID - S0301-472X(00)00172-7 [pii]
AID - 10.1016/s0301-472x(00)00172-7 [doi]
PST - ppublish
SO  - Exp Hematol. 2000 Jul;28(7):853-7. doi: 10.1016/s0301-472x(00)00172-7.