Recipient lymphocyte infusion in MHC-matched bone marrow chimeras induces a limited lymphohematopoietic host-versus-graft reactivity but a significant antileukemic effect mediated by CD8+ T cells and natural killer cells

Abstract

BackgroundChallenge of MHC-mismatched murine bone marrow chimeras with recipient-type lymphocytes (recipient lymphocyte infusion) produces antileukemic responses in association with rejection of donor chimerism. In contrast, MHC-matched chimeras resist eradication of donor chimerism by recipient lymphocyte infusion. Here, we investigated lymphohematopoietic host-versus-graft reactivity and antileukemic responses in the MHC-matched setting, which is reminiscent of the majority of clinical transplants. Design and MethodsWe challenged C3H→AKR radiation chimeras with AKR-type splenocytes (i.e. recipient lymphocyte infusion) and BW5147.3 leukemia cells. We studied the kinetics of chimerism using flowcytometry and the mechanisms involved in antileukemic effects using in vivo antibodymediated depletion of CD8 + T and NK cells, and intracellular cytokine staining. ResultsWhereas control chimeras showed progressive evolution towards high-level donor T-cell chimerism, recipient lymphocyte infusion chimeras showed a limited reduction of donor chimerism with delayed onset and long-term preservation of lower-level mixed chimerism. Recipient lymphocyte infusion chimeras nevertheless showed a significant survival benefit after leukemia challenge. In vivo antibody-mediated depletion experiments showed that both CD8 + T cells and NK cells contribute to the antileukemic effect. Consistent with a role for NK cells, the proportion of IFN-γ producing NK cells in recipient lymphocyte infusion chimeras was significantly higher than in control chimeras. ConclusionsIn the MHC-matched setting, recipient lymphocyte infusion elicits lymphohematopoietic hostversus-graft reactivity that is limited but sufficient to provide an antileukemic effect, and this is dependent on CD8 + T cells and NK cells. The data indicate that NK cells are activated as a bystander phenomenon during lymphohematopoietic T-cell alloreactivity and thus support a novel type of NK involvement in anti-tumor responses after post-transplant adoptive cell therapy.Key words: recipient lymphocyte infusion, antileukemic effect, CD8 T cells, NK cells. Citation: De Somer L, Sprangers B, Fevery S, Rutgeerts O, Lenaerts C, Boon L, Waer M, and Billiau AD. Recipient lymphocyte infusion in MHC-matched bone marrow chimeras induces a limited lymphohematopoietic host-versus-graft reactivity but a significant antileukemic effect mediated by CD8+ T cells and natural killer cells. Haematologica 2011;96(3):424-431. doi:10.3324/haematol.2010 This is an open-access paper. Recipient lymphocyte infusion in MHC-

Activated NKT Cells and NK Cells Render T Cells Resistant to Myeloid-Derived Suppressor Cells and Result in an Effective Adoptive Cellular Therapy against Breast Cancer in the FVBN202 Transgenic Mouse

“…A similar observation has been made in mice and humans with hematologic malignancies undergoing allogeneic stem cell transplantation. In the animal model, depletion of donor NK cells abrogated anti-leukemia effects of donor T cells (31). In humans, early donor derived NK cell recovery has been shown to be associated with a lower relapse risk in the non-myeloablative setting in the recipients of T cell replete allografts (32).…”

Cooperation of CD4+ T cells and CD8+ T cells and release of IFN-γ are critical for antileukemia responses of recipient mice treated by microtransplantation

“…Further studies indicated that CD8 + T cells were the major source of IFN-γ. Invariant/constant natural killer T (NK) T-cells, dendritic cells and NK cells, and the interaction among these different immune cells also participate in the antitumor process (11,22). The above course may be classified as host vs. graft (HVG) effects associated with massive systemic cytokine release.…”

Response to Comment on “Cutting Edge: CD8+ T Cell Priming in the Absence of NK Cells Leads to Enhanced Memory Responses”

“…For instance, depletion of the donor's NK cells abrogated antileukemia effects of the donor's T cells in the recipient of a stem cell transplant (3). NK cell recovery also preceded engraftment and expansion of the donor's T cells (4 1 T cells. We are happy to reply to the questions raised by Dr. Manjili and Dr. Toor regarding potential mechanisms behind our observations.…”

“…In a retrospective study, Panse and col-leagues (6) correlated the percentage of NK cells present in the infused HLA-matched transplant with T cell chimerism in the host, a parameter that is associated with a positive transplantation outcome. In contrast, De Somer and colleagues (4) have developed a mouse model to investigate lymphohematopoietic host-versus-graft reactivity and antileukemic responses in MHC-matched chimeras, a setting that may be reminiscent of the majority of clinical transplants. This study suggests that lymphohematopoietic alloreactivity provoked by adoptively transferred T cells provides a cytokine environment leading to NK cell activation and subsequent NK cellmediated killing of recipient tumor cells.…”