Proteasome Inhibition and Allogeneic Hematopoietic Stem Cell Transplantation: A Review

The proteasome and its associated ubiquitin protein modification system have proved to be an important therapeutic target in the treatment of multiple myeloma and other cancers. In addition to direct antitumor effects, proteasome inhibition also exerts strong effects on nonneoplastic immune cells. This indicates that proteasome inhibition, through the use of agents like bortezomib, could be used therapeutically to modulate immune responses. In this review we explore the emerging data, both preclinical and clinical, highlighting the importance of proteasome targeting of immunologic responses, primarily in the context of allogeneic hematopoietic stem cell transplantation (HSCT), both for the control of transplant-related toxicities like acute and chronic graft-versus-host disease (aGVHD, cGHVHD), and for improved malignant disease control after allogeneic HSCT

NK inhibitory-receptor blockade for purging of leukemia: Effects on hematopoietic reconstitution

AbstractOne of the obstacles of BMT that limits its efficacy is failure to eradicate the original tumor. The incidence of tumor relapse is particularly high after autologous BMT. Natural killer (NK) cells comprise various subsets that can express inhibitory receptors for MHC class I determinants. We have recently demonstrated that blockade of NK-cell inhibitory receptors can augment antitumor effects in vitro and in vivo. However, breakdown of tolerance and autoreactivity may occur as a result of the inhibition of NK-cell inactivation to self MHC determinants. We have utilized F(ab')2 fragments of monoclonal antibody, 5E6, against Ly49C/I inhibitory receptors, which are expressed on 35% to 60% of NK cells in H2b strains of mice and are specific for H2Kb, to investigate the effect of inhibitory-receptor blockade on syngeneic bone marrow cell (BMC) and tumor cell growth. We show that treatment of interleukin 2-activated C57BL/6 (B6, H2b) SCID-mouse NK cells with 5E6 F(ab')2 fragments during 48-hour coculture resulted in autoreactivity against syngeneic BMCs as demonstrated by suppression of myeloid reconstitution on day 14 post-BMT. However, this suppressive effect was transient and normalized by day 21 post-BMT. In contrast, blockade of inhibitory receptors during 24-hour coculture had no adverse effects on myeloid reconstitution after BMT. Furthermore, under the same coculture conditions, NK cell-mediated purging of C1498 leukemia cells contaminating syngeneic BMCs was more effective with inhibitory-receptor blockade, leading to a significantly higher proportion of animals with long-term survival compared to the control recipients. These results demonstrate that short-term in vitro blockade of inhibitory receptors can augment antitumor activity without long-term inhibitory effects on BMCs and thus may be of potential use in the purging of contaminating tumor cells prior to autologous BMT.Biol Blood Marrow Transplant 2002;8(1):17-25

Suppression of NK Cell-Mediated Bone Marrow Cell Rejection by CD4+CD25+ Regulatory T Cells: Linkage of Adaptive to Innate Responses

Abstract While a link between the innate to adaptive immune system has been established, studies demonstrating direct effects of T cells in regulating Natural Killer (NK) cell function have been lacking. Naturally occurring CD4+CD25+ regulatory T cells (Tregs) have been shown to potently inhibit adaptive responses by T cells. We therefore investigated whether Tregs could affect NK cell function in vivo. Using a bone marrow transplantation (BMT) model of hybrid resistance, in which parental (H2d) marrow grafts are rejected by the NK cells of the F1 recipients (H2bxd), we demonstrate that the in vivo removal of host Tregs significantly enhances NK-cell mediated BM rejection. This heightened rejection was mediated by the specific NK cell Ly-49+ subset previously demonstrated to reject the BMC in this donor/host pairing. The depletion of Tregs could also further increase rejection already enhanced by treating recipients with the NK cell activator, poly I:C. Although splenic NK cell numbers were not significantly altered, increased splenic NK in vitro cytotoxic activity was observed from the recovered cells. The regulatory role of Tregs was confirmed in adoptive transfer studies in which transferred CD4+CD25+ Tregs resulted in abrogation of NK cell-mediated hybrid resistance. Thus, Tregs can potently inhibit NK cell function in vivo and their depletion may have therapeutic ramifications with NK cell function in BMT and cancer therapy

Suppression of natural killer cell-mediated bone marrow cell rejection by CD4(+)CD25(+) regulatory T cells

Naturally occurring CD4(+)CD25(+) T regulatory (Treg) cells have been shown to inhibit adaptive responses by T cells. Natural killer (NK) cells represent an important component of innate immunity in both cancer and infectious disease states. We investigated whether CD4(+)CD25(+) Treg cells could affect NK cell function in vivo by using allogeneic (full H2-disparate) bone marrow (BM) transplantation and the model of hybrid resistance, in which parental marrow grafts are rejected solely by the NK cells of irradiated (BALB/c × C57BL/6) F(1) recipients. We demonstrate that the prior removal of host Treg cells, but not CD8(+) T cells, significantly enhanced NK cell-mediated BM rejection in both models. The inhibitory role of Treg cells on NK cells was confirmed in vivo with adoptive transfer studies in which transferred CD4(+)CD25(+) cells could abrogate NK cell-mediated hybrid resistance. Anti-TGF-β mAb treatment also increased NK cell-mediated BM graft rejection, suggesting that the NK cell suppression is exerted through TGF-β. Thus, CD4(+)CD25(+) Treg cells can potently inhibit NK cell function in vivo, and their depletion may have therapeutic ramifications for NK cell function in BM transplantation and cancer therapy