The ability of peripheral blood mononuclear cells (PBMC) to produce and respond to interleukin-2 (IL-2) was evaluated in 50 recipients of HLA- identical bone marrow (BM) depleted of mature T cells by soybean agglutination and E rosetting (SBA-E-BM). In contrast to our previous findings in recipients of unfractionated marrow, during weeks 3 to 7 post-SBA-E-BM transplantation (BMT), PBMC from the majority of patients spontaneously released IL-2 into the culture medium. This IL-2 was not produced by Leu-11+ natural killer cells, which were found to be predominant in the circulation at this time, but by T11+, T3+, Ia antigen-bearing T cells. The IL-2 production could be enhanced by coculture with host PBMC frozen before transplant but not by stimulation with mitogenic amounts of OKT3 antibody, thus suggesting an in vivo activation of donor T cells or their precursors by host tissue. Spontaneous IL-2 production was inversely proportional to the number of circulating peripheral blood lymphocytes and ceased after 7 to 8 weeks post-SBA-E-BMT in most of the patients. In patients whose cells had ceased to produce IL-2 spontaneously or never produced this cytokine, neither coculture with host cells nor stimulation with OKT3 antibody thereafter induced IL-2 release through the first year posttransplant. Proliferative responses to exogenous IL-2 after stimulation with OKT3 antibody remained abnormal for up to 6 months post-SBA-E-BMT, unlike the responses of PBMC from recipients of conventional BM, which responded normally by 1 month post-BMT. However, the upregulation of IL- 2 receptor expression by exogenous IL-2 was found to be comparable to normal controls when tested as early as 3 weeks post-SBA-E-BMT. Therefore, the immunologic recovery of proliferative responses to IL-2 and the appearance of cells regulating in vivo activation of T cells appear to be more delayed in patients receiving T cell-depleted BMT. Similar to patients receiving conventional BMT, however, the ability to produce IL-2 after mitogenic stimulation remains depressed for up to 1 year after transplantation.
During the early period following bone marrow transplantation before the immune system has reached full functional maturity, unprimed, nonspecific lytic systems may play a critical role as antiviral or antitumor effectors. The reconstitution of cells with this potential is of particular importance in recipients of bone marrow that has been depleted of mature T lymphocytes to prevent graft v host disease (GVHD). We examined the recovery of natural killer (NK) cells and interleukin 2 (IL 2)-augmented lymphokine-activated killer cells (LAK) in 48 patients at various intervals following transplantation of bone marrow depleted of mature cellular elements by treatment with soybean agglutinin and sheep RBCs (SBA-E- BMT). We found normal levels of both NK and LAK activity as early as 3 weeks following SBA-E- BMT. When compared with cells from controls, NK and LAK precursors from transplant recipients appeared to be activated in vivo in that freshly isolated peripheral blood mononuclear cells (PBMCs) from patients had an elevated cytolytic activity toward NK-insensitive targets and a more rapid response to activation by IL 2. In patients as well as controls, both LAK precursors and LAK effectors lacked antigens present on mature T lymphocytes (CD3, CD4, or CD8) but expressed antigens present on NK cells (CD2, CD16, and NKH1A). The LAK cells did not lyse either donor or host peripheral blood T cell targets. The activity of NK effectors but not LAK precursors survived the in vivo total body irradiation used for pretransplant conditioning in three patients studied. LAK precursors could be demonstrated as early as 18 days following transplant at a time when the bone marrow contained primarily donor- derived cells. Little or no LAK activity could be generated from cells of the SBA-E- BM graft itself, suggesting that LAK precursors differentiate rapidly from more primitive progenitors in the marrow graft. Thus, our data indicate that the NK and LAK lytic systems are among the earliest activities to recover during immune reconstitution following T cell-depleted BMTs.
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