Human bone marrow (BM) failure mediated by the immune system can be modeled in mice. In the present study, infusion of lymph node (LN) cells from C57BL/6 mice into C.B10-H2b/LilMcd (C.B10) recipients that are mismatched at multiple minor histocompatibility Ags, including the immunodominant Ag H60, produced fatal aplastic anemia. Declining blood counts correlated with marked expansion and activation of CD8 T cells specific for the immunodominant minor histocompatibility Ag H60. Infusion of LN cells from H60-matched donors did not produce BM failure in C.B10 mice, whereas isolated H60-specific CTL were cytotoxic for normal C.B10 BM cells in vitro. Treatment with the immunosuppressive drug cyclosporine abolished H60-specific T cell expansion and rescued animals from fatal pancytopenia. The development of BM failure was associated with a significant increase in activated CD4+CD25+ T cells that did not express intracellular FoxP3, whereas inclusion of normal CD4+CD25+ regulatory T cells in combination with C57BL/6 LN cells aborted H60-specific T cell expansion and prevented BM destruction. Thus, a single minor histocompatibility Ag H60 mismatch can trigger an immune response leading to massive BM destruction. Immunosuppressive drug treatment or enhancement of regulatory T cell function abrogated this pathophysiology and protected animals from the development of BM failure.

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IntroductionRecently, interest has grown in exploring the potential of natural killer (NK) cell-based immunotherapy regimens that use cellular effectors with antigen-independent tumor cytotoxicity. 1 In vitro data, 2-4 murine studies, 3,5 retrospective data from allogeneic transplantation trials, [6][7][8] and clinical trials evaluating adoptive allogeneic NK-cell infusions in patients with cancer 9 have implicated a therapeutic role of NK cells in the treatment of malignant diseases. However, a number factors limit the ability of NK cells to kill malignant cells. Several studies have shown that Treg cells exert contact and TGF-␤-dependent suppressive effects on endogenous NK-cell function. Athymic mice that lack Treg cells have long been known to have augmented NK-cell function. 10 Similarly, severe combined immunodeficiency (SCID) mice have heightened NK cell-mediated rejection of allogeneic bone marrow cells that can be suppressed by infusing Treg cells. 11,12 NK cell-inhibitory killer immunoglobulin-like receptors (KIRs) are also thought to be an important mechanism limiting the antitumor effects of autologous NK cells. Although allogeneic KIR ligand-incompatible NK cells may have greater tumor cytotoxicity than autologous NK cells, intense host immunosuppression must first be given before any measurable NK-cell engraftment can be achieved. 9 Tumors can also use several KIR-independent mechanisms to evade NK-cell recognition and killing, including loss or down-regulation of ICAM-1 and NKG2D ligands, increased expression of granzyme B inhibitors, and HLA-E-dependent NK-cell inactivation. [13][14][15][16][17][18][19] One strategy that has been recently explored to enhance the cytotoxic effects of adoptively infused NK cells is rendering tumor cells more susceptible to immune attack. Recently, we have shown that a variety of human tumors can be sensitized to lysis by autologous NK cells by pretreating malignant cells with the proteasome inhibitor bortezomib. 20 In vitro studies showed that bortezomib up-regulated surface expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors on tumor cells, enhancing their susceptibility to lysis by NK-cell TRAIL. Importantly, most tumors sensitized to NK cells had high major histocompatibility complex (MHC) class I surface expression, suggesting that bortezomib treatment could offset KIR ligand-mediated inhibition of autologous NK cells. Bortezomib has also been shown to reduce expression of cellular FLICE inhibitory protein (cFLIP) in several different human cancers, which also enhances TRAIL-mediated apoptosis. [21][22][23] In murine studies, bortezomib augments in vitro NK-cell purging of leukemia cells by syngeneic NK cells. 24 However, no data exists as to whether bortezomib can sensitize established tumors to the cytotoxic effects of adoptively infused NK cells in vivo. Likewise, no study has evaluated the effects of Treg cell depletion in a model of adoptive infusion of NK cells in recipients with established tumors.In the present study,...

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