Hematopoietic stem cell transplantation is a highly specialized and unique medical procedure. Autologous transplantation allows the administration of high-dose chemotherapy without prolonged bone marrow aplasia. In allogeneic transplantation, donor-derived stem cells provide alloimmunity that enables a graft-versus-tumor effect to eradicate residual disease and prevent relapse. The first allogeneic transplantation was performed by E. Donnall Thomas in 1957. Since then the field has evolved and expanded worldwide. New indications beside acute leukemia and aplastic anemia have been constantly explored and now include congenital disorders of the hematopoietic system, metabolic disorders, and autoimmune disease. The use of matched unrelated donors, umbilical cord blood units, and partially matched related donors has dramatically extended the availability of allogeneic transplantation. Transplant-related mortality has decreased due to improved supportive care, including better strategies to prevent severe infections and with the incorporation of reduced-intensity conditioning protocols that lowered the toxicity and allowed for transplantation in older patients. However, disease relapse and graft-versus-host disease remain the two major causes of mortality with unsatisfactory progress. Intense research aiming to improve adoptive immunotherapy and increase graft-versus-leukemia response while decreasing graft-versus-host response might bring the next breakthrough in allogeneic transplantation. Strategies of graft manipulation, tumor-associated antigen vaccinations, monoclonal antibodies, and adoptive cellular immunotherapy have already proved clinically efficient. In the following years, allogeneic transplantation is likely to become more complex, more individualized, and more efficient.

Microbiome-derived metabolites influence intestinal homeostasis and regulate graft-versus-host disease (GVHD), but the molecular mechanisms remain unknown. Here we show the metabolite sensor G-protein-coupled receptor 43 (GPR43) is important for attenuation of gastrointestinal GVHD in multiple clinically relevant murine models. GPR43 is critical for the protective effects of short-chain fatty acids (SCFAs), butyrate and propionate. Increased severity of GVHD in the absence of GPR43 is not due to baseline differences in the endogenous microbiota of the hosts. We confirm the ability of microbiome-derived metabolites to reduce GVHD by several methods, including co-housing, antibiotic treatment, and administration of exogenous SCFAs. The GVHD protective effect of SCFAs requires GPR43-mediated ERK phosphorylation and activation of the NLRP3 inflammasome in non-hematopoietic target tissues of the host. These data provide insight into mechanisms of microbial metabolite-mediated protection of target tissues from the damage caused allogeneic T cells.

Preliminary reports indicate that products of human mononuclear phagocytes may contribute to the infertility associated with endometriosis. To determine whether the generation of reactive oxygen metabolites by blood monocytes and peritoneal macrophages is altered in women with endometriosis, the present study evaluated luminol-enhanced chemiluminescence (CL) in cells at rest and following stimulation with phorbol myristate acetate (PMA) or serum-opsonized zymosan (SOZ). Peripheral venous blood and peritoneal fluid samples were collected from 60 infertile women undergoing diagnostic laparoscopy at midluteal phase and mononuclear phagocytic cell fractions were obtained by density gradient centrifugation. Whereas there was no significant difference between resting CL values in peripheral blood monocytes collected from women with and without endometriosis, PMA- and SOZ-stimulated monocyte CL was significantly greater in endometriosis patients. In contrast, there was a significant elevation in resting CL values when peritoneal macrophages from endometriosis patients were compared with macrophages obtained from patients with normal pelvic organs. It appears that chronic stimulation of macrophages in the peritoneal cavity provokes constitutive release of large quantities of reactive oxygen products in women with endometriosis. This may occur secondary to the accumulation of activated monocytes into the peritoneal cavity.

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