Mixed Chimerism-Dependent Tolerance After Myeloablative Bone Marrow Transplantation

移植物抗宿主病（GVHD）是一种致命的、毁灭性的造血细胞并发症

Graft-versus-host disease (GVHD) is a lethal and devastating complication of hematopoietic cell transplantation (HCT) or bone marrow transplantation (BMT), where HCT/BMT constitutes a predominant and curative approach for the treatment of hematological malignancies and other disorders. Because of exposure to environmental agents, such as the carcinogen agent orange, members of the US Military are under risk to develop hematological malignancies during their years as active soldiers or later as veterans. GVHD is caused by donor (graft) T cell-mediated immune attack of recipient (host) tissues and also complicates the clinical picture after combined transplantation of bone marrow and a solid organ. Veterans are also under higher risk to develop end-stage solid organ failure that requires transplantation. Novel treatment strategies are needed in BMT/HCT patients to maintain the donor T lymphocyte-mediated anti-tumor immune (graft-versus-tumor (GVT) response and suppress the GVHD. In this context, therapeutic achievement of mixed chimerism, which is characterized by the presence of donor and recipient hematopoietic cell after transplantation, results in immune tolerance by donor T cells against the recipient and in regulation of GVHD. Mixed chimerism also tolerizes recipient’s immune cells against the donor, suppressing the rejection of solid organ graft after combined transplantation and reduces the use of toxic immune suppressive medications. Current clinical protocols mostly use nonmyeloablative preparation (lower dose of chemotherapy and/or radiation without completely eradicating recipient’s bone marrow cells) before the BMT/HCT to achieve mixed chimerism. This approach carries a high risk of tumor relapse. By contrast, we use myeloablative preparation (higher dose of chemotherapy and/or radiation with complete eradication of recipient’s bone marrow cells) in our BMT model with mixed chimerism, where the GVT response is preserved and the risk of cancer relapse is reduced. We induce mixed chimerism-dependent regulation of GVHD by modulation of intestinal immune pathways using a completely novel approach and with self-limited helminth colonization of the gut. We have shown before that helminths promote the generation of mixed chimerism by stimulating recipient cell Th2 signaling and Th2- dependent generation of TGFβ. In this application, in Aim #1 we propose to investigate the elements of Th2/TGFβ pathways critical to generation of mixed chimerism. In Aim #2, we will explore the role of different immune regulatory circuitries relevant to mixed chimerism-dependent regulation of GVHD and solid organ rejection. In Aim #3, we will investigate the effect of mixed chimerism-induced immune regulation on the GVT response using a mouse leukemia/lymphoma model syngeneic with the BMT recipient strain. Our long-term goals are to dissect immune regulatory pathways important in helminth-induced mixed chimerism and apply the knowledge to clinical transplantation. Live helminths have been safely administered to immune suppressed patients, and helminth products with immune regulatory properties have been discovered for potential use in clinical practice. Therefore, targeting helminth-modulated signaling pathways with small molecules, helminths or their products may be a safe, potent and novel approach to promote transplantation tolerance without using toxic immune suppressive medications and preserve the beneficial GVT effect.