Wednesday, May 1, 2024
5/1/2024
Project Summary The advent of non-factor replacement therapies like the bispecific antibody emicizumab has revolutionized care for previously untreated patients with hemophilia A as well as those with and without inhibitors (neutralizing anti- factor VIII (FVIII) antibodies). However, these therapies are only effective as a prophylaxis to prevent bleeding and do not treat bleeds or provide protection against bleeding during major surgeries, resulting in the continued need for replacement FVIII therapy. Thus, several critical concerns surrounding the immediate and long-term management of these patients, and especially those with inhibitors still remain in this new treatment era. It is recognized that patients can generate different immune responses to FVIII: (1) no antibodies, (2) non-neutralizing antibodies, (3) transient inhibitors (inhibitors that resolve without the need of therapeutic interventions and despite continued FVIII treatment), or (4) low or high inhibitor titers that persist or wane to undetectable levels when FVIII treatment is withdrawn. However, why patients form distinct inhibitor responses remains an enigma. Our preclinical data suggest that differential inhibitor responses maybe due to the engagement of distinct B cell pathways of antibody production, with transient or waning inhibitors resulting from the development of an extrafollicular B cell response to FVIII and persistent inhibitors from a classical germinal center B cell response. Corroborating this, clinical reports indicate that some patients with hemophilia A fail to generate an anamnestic response to FVIII and demonstrate a loss of inhibitor titers in the absence of FVIII treatment. As germinal center B cell responses are responsible for the production of life-long immunity that comes in the form of memory B cells and long-lived plasma cells, we hypothesize that the B cell response to FVIII in patients with waning inhibitors occurs through an extrafollicular B cell process, while persistent inhibitors are generated through the long proposed classical germinal center response. The current proposal is thus focused on gaining a mechanistic understanding of the extrafollicular B cell response to FVIII in patients with severe hemophilia A, the relationship between the type of B cell response a patient develops and their inhibitor status, and factors that associate with the formation of an extrafollicular or germinal B cell response to FVIII by evaluating the immune response to FVIII in severe hemophilia A patients with a history of inhibitors.
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