Selective CD4+ T-cell depletion does not prevent graft-versus-host disease.
Donor-derived CD4+ T cells may play a role in the development of graft-versus-host disease (GVHD) and graft-versus-leukemia reaction after allogeneic bone marrow transplantation (BMT). Therefore, we evaluated the effect of CD4+ T-cell depletion on GVHD and graft-versus-leukemia reaction after HLA-matched BMT. CD4 depletion was performed using anti-CD4 monoclonal antibodies and immunomagnetic beads, initially in small-scale experiments on bone marrow and granulocyte colony-stimulating factor-mobilized peripheral blood apheresis products. The result was elimination of the CD4+ T cells from both sources (0% and 2+/-1.4% CD4+ cells, respectively). Subsequently, we used this technique for large-scale negative selection of CD4+ T cells from bone marrow grafts of four consenting leukemic patients in relapse (ALL-3, ANLL-1) (M-3, F-1). The large-scale CD4+ T-cell depletion resulted in >98% (n=4) elimination of CD4+ cells. The resulting population included 17.7+/-4.6% CD3+ T cells, 8.9+/-2.5% CD8+ T cells, 0.1+/-0.1% CD16+ natural killer cells, and 2.3+/-3.2% CD34+ hematopoietic progenitor cells. Patients were transplanted with 2.84+/-1.31 x 10(8) viable cells/kg. They received cyclosporine starting on day -1 as GVHD prophylaxis. Engraftment was fast with a white blood cell count of >1 x 10(9)/L on day 13.2+/-0.5, an absolute neutrophil count of >0.5 x 10(9)/L on day 13.8+/-0.5, and a platelet count of >25 x 10(9)/L on day 26.5+/-6.8. Immunological reconstitution was normal, and peripheral blood phenotyping 3 weeks after BMT disclosed 49.0+/-5.0% CD3, 14.3+/-12.4% CD4, and 59.5+/-7.8% CD8 T cells in addition to 17.0+/-3.0% CD16+ and 9.0+/-3.0% CD56 natural killer cells. Three out of four patients developed very early grade IV GVHD beginning on day 12 (10-13) and died 2-4 months after BMT. One patient is alive and well with a follow-up of 36 months. We conclude that selective CD4 T-cell depletion does not prevent GVHD.
Department of Bone Marrow Transplantation, Hadassah University Hospital, Jerusalem, Israel. nagler@hadassah.org.IL
A
A
Nagler
R
R
Condiotti
C
C
Nabet
E
E
Naparstek
R
R
Or
S
S
Samuel
S
S
Slavin
D000293:Adolescent; D000328:Adult; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D002648:Child; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000601:surgery; D008212:Lymphocyte Depletion; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000601:surgery; D017211:Treatment Failure