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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Immune reconstitution at 6 months following T-cell depleted hematopoietic stem cell transplantation is predictive for treatment outcome.

BACKGROUND: Compared with allogeneic bone marrow, in cytokine mobilized blood stem cell grafts, the number of hematopoietic progenitors and lymphoid cells is higher. Consequently, we compared the immune reconstitution following these two transplant modalities in patients receiving T-cell depleted grafts for hematological malignancies and studied the impact of lymphocyte subset recovery on clinical outcome. METHODS: Conditioning for transplantation was radiation-based, while graft versus host disease prophylaxis was by ex vivo T-cell depletion with Campath-1 antibodies. Clinical parameters of patients receiving bone marrow or cytokine-mobilized progenitor cell transplants were reviewed with emphasis placed on defining infectious events and on the causes of treatment failure (relapse, graft failure, or any cause of death). The blood lymphoid subsets, as well as markers for memory and naive T cells, were sequentially studied by standard flow cytometry. Serum immunoglobulins (Ig) concentrations were also determined. RESULTS: The patient population included 15 females and 27 males with a median age of 32.5 (range 15-54) years. Source of human leukocyte antigen-identical sibling allogeneic grafts was bone marrow in 14 and peripheral blood (PBPC) in 28. The median follow-up was of 1,278 (range 47-2,466) days. Following hematopoietic recovery, within the first year, 28 patients were readmitted for pyrexial episodes, and four died of sepsis. In both groups, while the CD8+ subset recuperated rapidly, CD19 and CD4+ T cells remained significantly decreased even after 12 months, leading to persistently abnormal CD4:CD8 ratios. The median values of CD16+ and CD56+ (natural killer) cells remained normal throughout the study period. Despite the patients who were receiving PBPC grafts having significantly higher numbers of allogeneic mononuclear cells (x 10(8)/kg; median: 6.97; range 4.03-10.10 vs. 0.71; range 0.45-0.99; P<0.001) and colony-forming unit granulocyte-macrophages (CFU-GMs) (x 10(4)/kg; median: 27.75; range 0-196, 2 vs. 13.05; range 2.43-57; P<0.05), the recovery rate of B cells or T-cell subpopulations was similar to those receiving bone marrow transplantation (BMT). Double fluorescence studies showed that CD2/CD45RO and RA as well as CD4/CD45RO and RA remained subnormal even after 12 months follow-up. During the observation period, except for IgA, normal levels of immunoglobulins were detected. In all, 18 out of 42 patients failed therapy, and 14 patients died. Treatment failure occurred at a median of 270 (range 47-1,638) days and was significantly associated with low total lymphocyte count (P = 0.01), CD2 (P = 0.09), CD8 (P = 0.01), CD19 (P = 0.02), CD45RA (P = 0.05), and CD4/CD45RA (P = 0.01), when tested at 6 months from transplantation. CONCLUSIONS: After T-cell depleted allogeneic PBPC or BMT, no differences in the rate of immune recovery were detected. However, patients with specific subset abnormalities at 6 months from grafting had a significantly higher risk of treatment failure.[1]


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