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This dissertation provides an in-depth exploration into the treatment effectiveness for aplastic anemia using causal inference methods, structured around three pivotal research papers. Each paper contributes to a nuanced understanding of treatment impacts, specifically focusing on bone marrow transplantation (BMT) and prescription drugs, and the identification of optimal treatment strategies. The first paper, "Causal Inference Analysis for Assessing the Effect of Bone Marrow Transplantation on the One-Year Survival of Adult and Pediatric Aplastic Anemia Patients," sets the foundation. It examines the short-term effectiveness of BMT in both adult and pediatric patients, providing crucial insights into how this treatment affects survival rates within the first-year post-diagnosis. This analysis is instrumental in understanding the implications of BMT across different age groups. In the second paper, "Assessing the Effect of Bone Marrow Transplantation on the Survival of Adult Aplastic Anemia Patients for the First Five-Years After Initial Diagnosis: A Causal Inference Study," the focus shifts to a longer-term perspective. This study extends the survival analysis to five years, offering a comprehensive view of the sustained effects of BMT. This longitudinal approach helps in understanding the durability of the treatment's impact. The third paper, "Identification of Optimal Treatment on the One-Year Survival of Aplastic Anemia Patients: A Causal Inference Study," broadens the scope by comparing various treatment options. It seeks to identify the most effective treatment strategy for improving one-year survival rates in aplastic anemia patients, contributing to the decision-making process in clinical settings. These three papers collectively offer an in-depth, varied analysis of treatment effects in aplastic anemia, employing causal inference techniques to navigate complex data. Utilizing robust, clinically significant methods such as doubly robust estimators, our research reveals a marked improvement in survival rates for BMT recipients, particularly adults, over one year. The studies also recognize the typically more severe stages of illness in BMT patients, underscoring the need for assessing disease severity. Despite constraints like small sample sizes limiting variable adjustments, this research substantially progresses our comprehension of aplastic anemia treatments. This methodological approach guarantees solid, clinically pertinent insights, enhancing our grasp of treatment efficacy in this field.

Tolerogenic dendritic cells (TolDCs) are actively involved in the elimination of autoreactive T cells in the thymus and quench T cell responses to self-antigens in the periphery under steady state. Normal dendritic cell (DC) maturation is influenced by both the inflammatory milieu and foreign antigens, and is required to generate an immunogenic response. These immunogenic DCs then interact with T and B cells to assist in antibody production. An imbalance between TolDCs and immunogenic DCs may instigate the development of autoimmunity and therefore, TolDCs have emerged as an expedient therapeutic target to manage autoimmunity. Although there is enough scientific evidence available depicting the development and functional utility of TolDCs in preclinical models of autoimmunity, in the absence of a more thorough understanding of TolDC biology their clinical use remains limited. This research work explores the immunomodulatory functions of TolDCs and the discovery of new possible therapeutic targets for the treatment of autoimmunity and provide three major insights. First, the protocol that we established in this thesis will help investigators to evaluate the capacity of new agents to promote the induction of TolDCs and to facilitate the effort to broaden the scope of TolDC therapeutics. Second, our data reveal that DCs are one of the principal cellular mediators of the immunomodulatory responses to the synthetic triterpenoid, CDDO-DFPA, and to related small molecules in the triterpenoid family for which we have shown efficacy in the preclinical model of multiple sclerosis. Third, we report that Nrf2 regulates DC tolerance by modulating their cytokine profile and cellular metabolism. Lastly our data show the therapeutic relevance of targeting Nrf2 signaling in the context of autoimmune disease. These data include analyses of Nrf2 function in preclinical models of multiple sclerosis (MS) and aplastic anemia (AA), and analyses of clinical specimens from patients with aplastic anemia, and together they help to further establish the therapeutic utility of TolDCs in managing clinical manifestations of these diseases. Overall, this is the first systematic research report revealing the Nrf2-dependent mechanisms of DC metabolic reprograming to generate tolerance and highlight their potential therapeutic utility in the treatment of autoimmunity.