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Research

Hemophilia Laboratory

Hemophilia LabThe focus of our research is on dissecting the immune response that induces inhibitor (IgG antibodies) development in patients diagnosed with congenital Hemophilia A. This x-linked bleeding disorder affects about 1/10,000 males resulting in low circulating levels of functional factor VIII (FVIII). The main disease manifestation is prolonged provoked bleeding (injury, trauma, surgery, etc.) as well as spontaneous bleeding. Treatment of bleedings is the replacement of the deficient factor through the use of exogenous FVIII concentrates. Of all patients with severe hemophilia A, about 20-30% develops inhibitors. Most inhibitors occur within the first 10-20 exposures to exogenous FVIII concentrates, usually within the first few years of life. A variety of factors, both genetic and environmental, are involved in the development of inhibitors.

Hemophilia LabLittle is known about how different aspects of B-cell activation can individually or synergistically lead to the development of inhibitors. Supports provide by T-cells have been proven crucial to the process. A possible lack or dysfunction of regulatory T-cells in controlling the pathologic immune response associated with FVIII has been proposed to explain inhibitors appearance. The environment in which B-cells are activated and the type of co-receptors molecules engaged in the activation also shaped the magnitude and the quality of response leading to inhibitor production. Ongoing projects in the Hemophilia laboratory include delineation of B-cell functional phenotypes and evaluation of the impact of T-regulatory cells on inhibitors development in patients with hemophilia A. In fact, B-cells appropriately activated through both the B-cell receptor (BCR) and CD40 produce high levels of IL-6, TNF-α, and LT-α, a combination that promotes germinal center development and amplifies T-cell responses. In contrast, bystander B-cells activated through CD40-mediated T-cell stimulation without earlier antigen/BCR engagement produce insignificant amounts of pro-inflammatory cytokines, but secrete significant levels of the immune regulatory cytokine IL-10, which would act to suppress the local inflammatory response. One of our key goals is to evaluate whether in Hemophilia A patients, inappropriate activation of B-cells is at play and/or if intrinsic characteristics of B-cells (proportion of subtypes and sensitivity to stimuli) predispose some patients to develop inhibitors.

Director:
Frederic Ganapamo, PhD

Laboratory Staff:
Ruijuan "Rachel" Gao, PhD
Medical Research Specialist

Telephone:
504-988-0341


 

 

1430 Tulane Ave, New Orleans, LA 70112 504-988-5187 medsch@tulane.edu