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Biotech / Medical : Biotransplant(BTRN) -- Ignore unavailable to you. Want to Upgrade?

To: Pierre Borczuk who wrote (801)	12/4/2000 9:18:33 AM
From: Pierre Borczuk	Read Replies (1) \| Respond to of 1475

[2244] EARLY PREDOMINANCE OF HOST OR DONOR T-CELLS CORRELATES WITH GRAFT FAILURE AND GVHD, RESPECTIVELY, IN RECIPIENTS OF EXTENSIVELY HLA-MISMATCHED BONE MARROW TRANSPLANTS FOLLOWING NON-MYELOABLATIVE CONDITIONING. A. Kratz, S.I. Alexander, S.L. McAfee, H. Grossberg, R. Sackstein, C. Colby, I. Hope, F.I. Preffer, S.L. Saidman, D. Weymouth, D. Dombkowski, D.H. Sachs, T.R. Spitzer, M. Sykes Transplantation Biology Research Center; BMT Unit; Department of Pathology, Massachusetts General Hospital/Harvard Medical School, and BioTransplant Inc., Boston, MA, USA We studied engraftment and immune recovery in patients with advanced hematologic malignancies receiving non-myeloablative conditioning before HLA-mismatched BMT. The aim was adequate donor and host T cell depletion to prevent GvHD while allowing the development of mixed chimerism, with the intention of giving donor leukocyte infusions later to achieve GvL effects. Seven patients received two different regimens involving a humanized anti-CD2 monoclonal antibody, MEDI-507. Four patients received 0.1 mg/kg MEDI-507 on day -2 and 0.6 mg/kg on days -1, 0 and 1 (regimen A). Three patients received 0.1 mg/kg MEDI-507 on day -7 and 0.6 mg/kg on days -6 and -5 (regimen B). In addition, all patients received cyclophosphamide (50 mg/kg/day on days -5, -4, and -3) and cyclosporine beginning on day -1. Five of the seven patients received thymic irradiation (7 Gy) on day -1. WBCs were studied by flow cytometry for chimerism and phenotype. On day 28, mean T-cell counts of patients on regimen A were substantially lower than on regimen B (4±2.6 vs. 138±160 T cells/mm3 (p=0.06). The average number of B cells (0 and 3 B cells/mm3, p=0.2) and of NK cells (46 and 81 NK cells/mm3, p=0.9) in the two groups were similar. CD4 counts were 1±0.7 in regimen A and 49±36/mm3 in regimen B (p=0.06). CD8 counts were 3±2/mm3 in regimen A and 96±128/mm3 in regimen B (p=0.1). Most (62-99%) of the T-cells present on day 28 in patients on regimen A were host-derived. In contrast, in two of the three patients on regimen B, most T-cells (60% and 97%) were donor-derived. The activation marker CD25 was expressed on average by 63% and 61% of the CD4 T-cells in the two treatment groups, compared to only 6% and 4% of CD8, respectively. All patients showed initial mixed chimerism in all WBC lineages, but in the four patients on regimen A, chimerism subsequently became undetectable by days 21, 47, 70 and 100. In contrast, chimerism was sustained through day 100 in two of the three patients on regimen B; these were the patients with predominantly donor-derived T-cells on day 28. The majority (69% and 94%) of the CD25+ CD4 cells in these patients were donor-derived on day 28. The third patient on regimen B, whose T-cells on day 28 were predominantly (95%) host-derived (62% CD25+), lost chimerism by day 35. While none of the patients in regimen A developed GvHD, the two patients with sustained chimerism on regimen B developed acute GvHD (one grade II, one grade IV). Our results suggest that early predominance of donor T-cells is correlated with sustained chimerism, but also with GvHD, and that an early predominance of host T-cells portends graft failure. Host or donor T cells escaping depletion with MEDI-507 may play a critical role in graft loss and in the development of GvHD, respectively. The expression of CD25 on CD4 cells only raises the possibility that this subset plays the major role in graft rejection and GvHD in HLA-mismatched BMT with this protocol. Keywords: Transplantation, bone marrow; Graft-vs-host disease