Allogeneic stem cell bone marrow transplantation can be used to cure some malignancies, genetic immunodeficiencies, hemoglobinopathies, and autoimmune disease. Widespread application of this therapy is not yet realized because of its potential serious complications, most notably graft- versus-host disease (GvHD). Therefore, innovative therapies to both prevent and treat acute GvHD (aGvHD) that are effective and have fewer side effects, particularly for steroid refractory patients are urgently needed. Physiological processes such as pregnancy provide a clue to novel interventions to significantly reduce aGvHD mortality. Contrary to old perceptions, data gathered over the last years has shown that pregnancy is not a state of immunosuppression, rather during pregnancy there are qualitative changes in the immune response at the maternal-fetal interface and systemically. These changes are required to tolerate the semi-allogeneic fetus while protecting the mother from infections. Soluble factors secreted by trophoblast cells of the placenta contribute to the establishment of the tolerogenic immune environment during pregnancy. PSG1 is such a factor and is the most abundant trophoblastic protein in maternal blood during human pregnancy. We have shown that PSG1 is among the few known activators of the immune-regulatory cytokine transforming growth factor beta (TGF-?), which is secreted from cells in a latent/inactive form. TGF-? regulates the phenotype and function of cells of the innate and adaptive immune systems and down regulates the expression of pro-inflammatory cytokines by these cells. In addition, TGF-? is required for the induction and maintenance of regulatory CD4+ Foxp3+ T cells (Tregs). In two in vivo mouse models, we showed that PSG1-mediated increase in active TGF-?1 results in an increase in the absolute number and percentage of Tregs. Tregs have a well demonstrated beneficial effect in the context of aGvHD while their increase does not prevent the graft-versus-leukemia effect of donor lymphocytes. Therefore increasing the number of Tregs to decrease mortality associated with aGVHD is considered a novel and valid strategy for all current pathologies requiring bone marrow transplantation. However, protocols for in vitro Treg expansion are costly and time-consuming limiting their clinical use. To circumvent these problems, increasing the Treg cell numbers in vivo provides a valuable alternative. Therefore, we propose that PSG1 administration has a previously unexplored therapeutic potential due to its immune-regulatory function and its lack of toxicity or side effects, supported by the high serum concentration of this protein found during normal pregnancy. To test our hypothesis, we will administer recombinant PSG1 or a control protein in a pre-clinical model to achieve the following aims: 1) Evaluate the potential therapeutic effects of treatment with PSG1 in preventing acute graft-versus-host disease and define its mechanism of action and 2) Determine whether administration of PSG1 preserves the graft-versus-tumor activity of donor cells following allogeneic hematopoietic bone marrow transplantation.
This proposal addresses the characterization and potential use of a biological protein as a novel therapeutic option for the treatment of acute-graft-versus host disease, a syndrome caused by donor T cells that attack several organs following allogeneic hematopoietic stem cell transplantation. Unlike current therapeutic approaches that involve generalized immune suppression, this approach will likely result in an increase in the number of regulatory T cells and a decrease in the secretion of pro-inflammatory cytokines.
|Jones, Karlie; Bryant, Sarah; Luo, Jian et al. (2018) Recombinant Pregnancy-Specific Glycoprotein 1 Has a Protective Role in a Murine Model of Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant :|