Achievement of Tolerance Induction to Prevent Acute Graft-vs.-Host Disease

Acute graft-vs.-host disease (GVHD) limits the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT), a main therapy to treat various hematological disorders. Despite rapid progress in understanding GVHD pathogenesis, broad immunosuppressive agents are most often used to prevent and remain the first line of therapy to treat GVHD. Strategies enhancing immune tolerance in allo-HSCT would permit reductions in immunosuppressant use and their associated undesirable side effects. In this review, we discuss the mechanisms responsible for GVHD and advancement in strategies to achieve immune balance and tolerance thereby avoiding GVHD and its complications

Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1–/– donors. PD-L1–deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1–/– donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell–mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD

Co-inhibitory molecules: Controlling the effectors or controlling the controllers?

Nearly forty years ago the concept was proposed that lymphocytes are negatively regulated by what are now called co-inhibitory signals. Nevertheless, it is only the more recent identification of numerous co-inhibitors and their critical functions that has brought co-inhibition to the forefront of immunologic research. Although co-inhibitory signals have been considered to directly regulate conventional T cells, more recent data has indicated a convergence between co-inhibitory signals and the other major negative control mechanism in the periphery that is mediated by regulatory T cells. Furthermore, it is now clear that lymphocytes are not the sole domain of co-inhibitory signals, as cells of the innate immune system, themselves controllers of immunity, are regulated by co-inhibitors they express. Thus, in order to better understand negative regulation in the periphery and apply this knowledge to the treatment of disease, a major focus for the future should be the definition of the conditions where co-inhibition controls effector cells intrinsically versus extrinsically (via regulatory or innate cells)

Tackling cancer cell dormancy: Insights from immune models, and transplantation

Disseminated non-dividing (dormant) cancer cells as well as those in equilibrium with the immune response remain the major challenge for successful treatment of cancer. The equilibrium between disseminated dormant cancer cells and the immune system is reminiscent of states that can occur during infection or allogeneic tissue and cell transplantation. We discuss here the major competing models of how the immune system achieves a self nonself discrimination (pathogen/danger patterns, quorum, and coinhibition/tuning models), and suggest that taking advantage of a combination of the proposed mechanisms in each model may lead to increased efficacy in tackling cancer cell dormancy

Prior to Peripheral Tolerance, Newly Generated CD4 T Cells Maintain Dangerous Autoimmune Potential: Fas- and Perforin-Independent Autoimmunity Controlled by Programmed Death-1

Lymphopenia can result from various factors, including viral infections, clinical interventions, or as a normal property of the fetal/neonatal period. T cells in a lymphopenic environment undergo lymphopenia-induced proliferation (LIP) to fill the available “niche” as defined by peptide–MHC and homeostatic cytokine resources. We recently reported systemic autoimmunity following reconstitution of the lymphoid compartment of Rag1−/− mice with PD-1−/− hematopoietic stem cells or by transfer of thymocytes, but not splenocytes, suggesting that programmed death-1 (PD-1) plays a crucial role in controlling recent thymic emigrants (RTE) and preventing autoimmunity upon their LIP. However, it is unclear whether RTE residing within the periphery of a lymphoreplete host maintain enhanced autoimmune generating potential or if this property only manifests if RTE experience a lymphopenic periphery immediately after export from the thymus. Furthermore, it is unclear which of a variety of T cell effector mechanisms generate pathology when control of RTE by PD-1 is lacking. Herein, we determined that PD-1 is upregulated on CD4 T cells undergoing the natural LIP characteristic of the neonatal period. Newly generated T cells lacking PD-1 maintained an enhanced autoimmune potential even after residence in a lymphoreplete periphery, emphasizing the importance of PD-1 in the establishment of peripheral tolerance. Neither Fas nor perforin-dependent killing mechanisms were required for autoimmunity, while host MHC-II expression was critical, suggesting that LIP-driven autoimmunity in the absence of PD-1 may primarily result from a CD4 T cell-mediated systemic cytokinemia, a feature potentially shared by other autoimmune or inflammatory syndromes associated with immune reconstitution and LIP

Influence of photon energy on the quality of prostate intensity modulated radiation therapy plans based on analysis of physical indices

The goal of the present study was to study the effects of low- and high-energy intensity-modulated photon beams on the planning of target volume and the critical organs in cases of localized prostate tumors in a cohort of 8 patients. To ensure that the difference between the plans is due to energy alone, all other parameters were kept constant. A mean dose volume histogram (DVH) for each value of energy and for each contoured structure was created and was considered as completely representative for all patients. To facilitate comparison between 6-MV and 15-MV beams, the DVH-s were normalized. The different parameters that were compared for 6-MV and 15-MV beams included mean DVH, different homogeneity indices, conformity index, etc. Analysis of several indices depicts more homogeneous dose for 15-MV beam and more conformity for 6-MV beam. Comparison of all these parameters showed that there was little difference between the 6-MV and 15-MV beams. For rectum, 2 to 4 % more volume received high dose with the 6-MV beam in comparison with the 15-MV beam, which was not clinically significant, since in practice much tighter constraints are maintained, such that Normal Tissue Complication Probability (NTCP) is kept within 5 %. Such tighter constraints might increase the dose to other regions and other critical organs but are unlikely to increase their complication probabilities. Hence the slight advantages of 15-MV beam in providing benefits of better normal-tissue sparing and better coverage cannot be considered to outweigh its well-known risk of non-negligible neutron production

Dendritic Cell Expression of Retinal Aldehyde Dehydrogenase-2 Controls Graft-versus-Host Disease Lethality

Recent studies have underscored the critical role of retinoic acid (RA) in the development of lineage-committed CD4 and CD8 T cells in vivo. We have shown that under acute graft-versus-host disease (GVHD) inflammatory conditions, RA is upregulated in the intestine and is proinflammatory, as GVHD lethality was attenuated when donor allogeneic T cells selectively expressed a dominant negative RA receptor α that blunted RA signaling. RA can function in an autocrine and paracrine fashion, and as such, the host cell lineage responsible for the production of RA metabolism and the specific RA-metabolizing enzymes that potentiate GVHD severity are unknown. In this study, we demonstrate that enhancing RA degradation in the host and to a lesser extent donor hematopoietic cells by overexpressing the RA-catabolizing enzyme CYP26A1 reduced GVHD. RA production is facilitated by retinaldehyde isoform-2 (RALDH2) preferentially expressed in dendritic cells (DCs). Conditionally deleted RA-synthesizing enzyme RALDH2 in host or to a lesser extent donor DCs reduced GVHD lethality. Improved survival in recipients with RALDH2-deleted DCs was associated with increased T cell death, impaired T effector function, increased regulatory T cell frequency, and augmented coinhibitory molecule expression on donor CD4+ T cells. In contrast, retinaldehydrogenase isoform-1 (RALDH1) is dominantly expressed in intestinal epithelial cells. Unexpectedly, conditional host intestinal epithelial cells RALDH1 deletion failed to reduce GVHD. These data demonstrate the critical role of both donor and especially host RALDH2+ DCs in driving murine GVHD and suggest RALDH2 inhibition or CYP26A1 induction as novel therapeutic strategies to prevent GVHD