PIDTC Project 6906 PIRD ? Abstract Primary Immune Regulatory Disorders (PIRD) are a group of immune diseases characterized predominantly by immune dysregulation leading to organ-specific autoimmunity, excessive inflammation, and non-malignant lymphoproliferation. Unlike classical primary immunodeficiencies, susceptibility to infections is typically less prominent in these disorders. Causal gene defects that impact critical immune regulatory mechanisms, e.g. regulatory T cell (Treg) function, key cytokine signaling pathways, and vital growth and differentiation mechanisms, have now been identified in many patients with PIRD. Examples include FOXP3 in the Immune dysregulation, Polyendocrinopathy, Enteropathy, X--linked (IPEX) syndrome, CTLA4 in CTLA4 haplo- insufficiency, STAT1 and STAT3 in STAT1 or STAT3 gain-of-function (GOF) diseases, but there are now many others. In fact, disorders with a PIRD phenotype constitute the fastest growing subset of newly-identified genetic immunodeficiencies. The clinical severity of PIRD disorders often requires aggressive therapy to prevent long-term damage, disability, or death. There is, however, no consensus regarding the best approach to diagnose and treat PIRD, including which immune modulating drugs are most effective, and whether hematopoietic cell transplantation (HCT) can be curative. We and others have shown that HCT can be curative for some PIRD disorders. There is however no consensus regarding the best HCT approach and little information about the unique challenges of HCT in PIRD. There also remains a significant need to define key clinical and laboratory features that distinguish patients who will benefit most from HCT or from targeted immunomodulatory treatments. We propose to evaluate the spectrum of clinical presentations, disease evolution, therapeutic responsiveness, HCT approaches, HCT outcomes, and quality of life in PIRD patients. The objective of this proposal is to answer key questions related to the diagnosis, care, and outcome of PIRD, while also investigating basic mechanisms of disease pathogenesis and therapeutic responsiveness. All patients will be identified based on a defined set of clinical criteria. Some patients who meet these criteria will have a defect in a gene known to be associated with PIRD, while others will not. Patients will be evaluated together as a cohort and subanalyses will be performed to compare patients with and without an identified genetic defect. The impact of the proposed research is that it will answer key questions that will 1) accelerate diagnosis and increase our understanding of this emerging subset of immune disorders; 2) directly guide the therapeutic approach utilized for PIRD; 3) lead to the design of clinical trials to establish new therapies, since several of the underlying molecular defects are already targets of immunomodulators under development or currently in use, and 4) inform the treatment of autoimmune disorders more broadly.
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