Our goal is to investigate mechanisms responsible for chronic graft versus host disease (cGVHD) development so that strategies for safer, more effective allogeneic hematopoietic stem cell transplantation (HCT) can be implemented. While work by us and others has revealed that B cells are key contributors to cGVHD pathogenesis, the immune mechanisms responsible for pathological B-cell activation remain undetermined. Also, how B cells mediate cGVHD remains unknown. Since immune reconstitution occurs in the setting of ubiquitous foreign antigen, ongoing removal of lymphocytes reactive to recipient tissues is imperative to achieve or maintain immune tolerance. In HCT patients, we previously discovered that excessive levels of a B- cell survival factor, B Cell Activating Factor (BAFF) is significantly associated with cGVHD development. Administration of B-cell specific antibody, rituximab, results in cGVHD amelioration, but only if robust recovery of a nave B cell compartment occurs, corroborating the importance of B cell homeostasis for cGVHD aversion. In cGVHD patients B cells, we found that BAFF-associated pathways constitutively signal. Chronic GVHD B cells are in vivo activated and primed for survival, suggesting a failure of the BAFF deletional tolerance checkpoint. Our central hypothesis is that B cells, that are able to overcome immune tolerance mechanisms during immune recovery, mediate cGVHD pathobiology. Our more recent preliminary data suggest that in cGVHD, potentially pathological B cells have a lowered B Cell Receptor (BCR) signaling threshold. An increased BCR responsiveness to surrogate antigen was associated with increases in the proximal BCR molecule levels, B-cell linker protein (BLNK) and Spleen tyrosine kinase (Syk). Chronic GVHD B cells were preferentially blocked by a small molecule inhibitor, revealing a mechanism underpinning aberrant B-cell activation in cGVHD and laying the foundation for our proposed clinical trials. Data also forward our corollary hypothesis that a lowered BCR signaling threshold in cGVHD patients may be due to excess BAFF. In this proposal we will utilize both murine models and human assays to test this hypothesis. We will also identify B cell subsets with disease-mediating function by testing how BAFF drives these B cells and whether aberrant B cells mediate T cell activation. Specifically, we aim to determine whether pathological B cells in cGVHD develop because of: 1) excess BAFF; 2) immediate Ag-responsiveness; and 3) failure of immune regulation by certain B cell subsets after HCT. This proposal includes co-investigator and B cell immunologist, Dr. Thomas Tedder, and co-investigators Drs. Rizzieri and Li along and their Duke clinical trial and statistical core facilities. When work is completed, we will have determined how and when BAFF-driven pathological B cells arise after HCT, so that targeted and preventative therapies can be effectively implemented in patients. Our long-term goal is to improve outcomes of patients with hematological malignancies and disorders with safe and effective allogeneic HCT.
Allogeneic hematopoietic cell transplantation (HCT) is the only known curative option for many of the approximately 40 per 100,000 Americans afflicted with life-threatening blood, bone marrow, or lymph node cancer. Immune pathology called chronic graft versus host disease (cGVHD) develops in 30-80% of HCT patients, carrying an impact on morbidity and survival that has not improved significantly over the last 30 years. The current research will advance knowledge about immunopathologic mechanisms in HCT that will impact cancer patients, and patients with autoimmune and blood disorders.
