Endogenously generated activated killer cells circulate after autologous and allogeneic marrow transplantation but not after chemotherapy

Abstract

After marrow transplantation, major histocompatibility complex (MHC)- unrestricted natural killer (NK) lymphocytes are among the first cells to appear in the circulation. After T-cell-depleted bone marrow transplantation (TD-BMT), these cells have an activated pattern of target cell killing; they also secrete lymphokines including gamma- interferon (gamma-IFN), interleukin-2 (IL-2), and tumor necrosis factor (TNF) and may have a significant role as a primary defense against viral reactivation and in the elimination of residual host malignancy. We studied 43 patients with hematologic malignancy, treated by allogeneic TD-BMT, autologous nondepleted BMT, or chemotherapy alone to investigate (a) the mechanisms underlying the generation of these activated killer cells, (b) the range of conditions under which they are produced, and (c) their surface phenotype. We showed that gamma-IFN- secreting activated killer cells with the capacity to kill MHC- nonidentical NK-resistant targets are generated 4 to 6 weeks after either allogeneic TD-BMT or autologous BMT but do not appear after treatment with chemotherapy. Production therefore is not owing to T- cell depletion per se or to host donor alloreactivity, nor is it caused by stimulation by alloantigens contained in blood product support since no significant difference exists between allograft and chemotherapy patients in the number of units of blood platelet support given in the posttreatment period. Because most patients had no evidence of stimulation from virus reactivation/infection, the phenomenon of activation therefore appears to represent posttransplant immune disregulation following repopulation of the host immune system with lymphoid subsets derived exclusively from blood and marrow. Activated killing is predominantly mediated by the CD16+ CD3- subset, but substantial activity remains in the CD16- CD3+ cell fraction. Monoclonal antibodies (MoAbs) that block interaction with class-I MHC molecules at the level of target cell (W6/32 anti-HLA class I) or effector cell (CD8) do not inhibit killing by CD16- CD3+ cells. Activated killer cells may contribute to the lower risk of relapse after marrow transplantation as compared with intensive chemotherapy.

Interferon‐γ+ and interleukin‐2+ T cells in peripheral blood from multiple myeloma patients in relation to disease status and maintenance therapy with interferon‐α2b (intron A)

“…In allogeneic transplantation, increases in plasma levels of both INFg and IL-2 have been associated with graft-versusleukaemia (Hauch et al, 1990;Chasty et al, 1993) and graftversus-host effects (Neiderweisser et al, 1990). Both of these cytokines increase NK activity which are thought to be the principal effectors in allogeneic transplants (Reittie et al, 1989;Hauch et al, 1990). In MM patients the contribution of NK cells to an autologous anti-tumour effect is unclear.…”

Improving the Outcome of Bone Marrow Transplantation by Using CD52 Monoclonal Antibodies to Prevent Graft-Versus-Host Disease and Graft Rejection

“…NK cells are relatively spared by CAMPATH-1, 41, 45 and it has been suggested that they may play a role in control of CMV disease and have an antileukemia effect. [46][47][48][49][50][51] However, B cells are efficiently depleted. Elsewhere, we have reported that T-cell depletion with CAMPATH-1 antibodies does not give rise to an excess of B-cell lymphoproliferative disorders, in contrast to some other methods of T-cell depletion.…”