Immune Mechanisms Important for the Pathogenesis of Acute Graft-versus-Host Disease Public Deposited

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Last Modified
  • March 21, 2019
Creator
  • Fulton, LeShara Malika
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Allogeneic stem cell transplantation is a standard treatment for patients with high-risk relapsed leukemia, aplastic anemia, congenital bone marrow failure syndromes, and relapsed or recurrent lymphoid malignancies. Over 20,000 allogeneic transplants are conducted annually worldwide, confirming its effectiveness as a treatment for patients with otherwise lethal malignancies. Cure rates range from 15-80% depending on preexisting conditions and diagnoses. Patients receive high dose chemotherapy to eliminate malignant cells and allow engraftment of donor cells. However, this intense treatment regimen leaves patients vulnerable to infections, relapse, and acute graft-versus-host disease (aGvHD). aGvHD is a disease characterized by selective epithelial damage to target organs. Complications from aGvHD result in increased morbidity and mortality in transplant recipients. aGvHD is initiated by mature CD4+ and CD8+ T cells present in the stem cell inoculum. These donor T cells replenish host T cell immunity and promote engraftment. Conversely, damage to target tissue, predominantly the skin, liver, and gastrointestinal tract, in aGvHD is caused by immunologically functional donor T lymphocytes that respond to genetic disparities in host antigens. Our laboratory has focused on the migration of T cells in aGvHD pathogenesis. Coronins are a family of seven-actin binding proteins found in all eukaryotic organisms. Functional data in non-mammalian systems have shown a role for Coronins in cell migration, motility, and cytokinesis. The most well studied of the proteins, Coronin 1A (Coro 1A) is expressed primarily in hematopoietic cells and the focus of our studies. Here, we demonstrate a requirement for Coro 1A in the pathogenesis of acute GvHD. Delayed entry and impaired egress from secondary lymphoid tissues were observed in T cells deficient in Coro 1A. Decreased expression of the C-C chemokine receptor type 7 (CCR7) and the signaling lipid receptor, sphingosine 1 phosphate receptor 1 (S1Pr1) were detected in Coro 1A deficient T cells. Egress to target aGvHD was limited by Coro 1A deficient cells due to accumulation in gastrointestinal lymph nodes. These data suggest that therapeutic approaches that prevent entry and egress from secondary lymphoid organs may effective treatment options for acute GvHD.
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  • In Copyright
Advisor
  • Serody, Jonathan
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill
Graduation year
  • 2013
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