Mechanisms of macrophage migration inhibitory factor (MIF)-dependent tumor microenvironmental adaptation.

Since its activity was first reported in the mid-1960s, macrophage migration inhibitory factor (MIF) has gone from a cytokine activity modulating monocyte motility to a pleiotropic regulator of a vast array of cellular and biological processes. Studies in recent years suggest that MIF contributes to malignant disease progression on several different levels. Both circulating and intracellular MIF protein levels are elevated in cancer patients and MIF expression reportedly correlates with stage, metastatic spread and disease-free survival. Additionally, MIF expression positively correlates with angiogenic growth factor expression, microvessel density and tumor-associated neovascularization. Not coincidentally, MIF has recently been shown to contribute to tumoral hypoxic adaptation by promoting hypoxia-induced HIF-1alpha stabilization. Intriguingly, hypoxia is a strong regulator of MIF expression and secretion, suggesting that hypoxia-induced MIF acts as an amplifying factor for both hypoxia and normoxia-associated angiogenic growth factor expression in human malignancies. Combined, these findings suggest that MIF overexpression contributes to tumoral hypoxic adaptation and, by extension, therapeutic responsiveness and disease prognosis. This review summarizes recent literature on the contributions of MIF to tumor-associated angiogenic growth factor expression, neovascularization and hypoxic adaptation. We also will review recent efforts aimed at identifying and employing small-molecule antagonists of MIF as a novel approach to cancer therapeutics.

Facilitating cells as a venue to establish mixed chimerism and tolerance.

Graft rejection and the toxicity associated with the use of non-specific immunosuppression remain the major limitations in pediatric solid organ transplantation. The induction of tolerance in transplant recipients is an elusive but achievable goal that will decrease the dependence on immunosuppressive agents. BMT is associated with a robust form of donor-specific transplantation tolerance. It achieves a state of chimerism, defined as the presence of donor marrow cells in the recipient. The two major toxicities in conventional bone marrow transplantation that have prevented its clinical application to induce tolerance are the toxicity of ablative conditioning and GVHD. Two forms of chimerism exist: full chimerism and mixed chimerism. In full chimerism, the hematopoietic system of the recipient is replaced by that of the donor following ablative conditioning. Full chimerism is associated with a relatively impaired immunocompetence for primary immune responses and an increased risk of GVHD. In addition, the 7-10% regimen-related mortality associated with ablation could not be accepted in solid organ allograft recipients. In mixed chimerism the donor hematopoietic system co-exists with that of the recipient. Mixed chimerism induces donor-specific tolerance and is associated with superior immunocompetence and a relative resistance to GVHD compared with full chimerism. Moreover, it can be achieved with partial conditioning, thereby reducing the regimen-related morbidity associated with myeloablation. Approaches to establish mixed chimerism using non-myeloablative-conditioning regimens have been aggressively pursued over the past decade. Mixed chimerism can be safely established with minimal conditioning, resulting in a significant reduction in risk compared with ablative conditioning. GVHD is the final hurdle that has prevented the widespread application of chimerism to induce tolerance. Donor T cells are the primary effector cells for GVHD. Although T cell depletion of the donor marrow avoids GVHD, it results in an increase in the rate of graft failure in MHC-disparate recipients. The dichotomy between GVHD and T cell depletion graft failure has recently been dissociated by the discovery of CD8+/TCR- graft FC. Purified HSC engraft readily in syngeneic recipients but not in MHC-disparate allogeneic recipients. The addition of small numbers of facilitating cells permits durable HSC engraftment in allogeneic recipients and avoids GVHD. Using FC to promote HSC engraftment following non-myeloablative conditioning could be a promising approach to establish tolerance in solid organ transplantation. This invited review focuses on recent developments in stem cell chimerism and tolerance that could bring the use of this approach to induce tolerance to solid organ transplantation one step closer to reality.