Clonal Loss of Human Leukocyte Antigen (HLA) Gene Expression and the Immunologic Basis of Acquired Aplastic Anemia
Abstract
Background: Acquired aplastic anemia (aAA) is one of the most common bone marrow failure diseases affecting both children and adults. aAA is an autoimmune disorder in which immune cells, known as T cells, destroy the bone marrow stem cells that are responsible for blood production. Patients with severe aAA develop life-threatening infections, require transfusions of red blood cells and platelets, and are at a high risk for developing myelodysplastic syndrome (MDS) and leukemia. While matched related donor bone marrow transplantation (MRDBMT) is a highly effective therapy option, most patients lack an eligible donor for MRD-BMT and have historically received immune suppression therapy (IST). IST produces a long-term cure in only 20-40% of patients, although patients cured by IST avoid the many potential short- and long-term side effects of bone marrow transplant. Exciting new therapy approaches, including new drugs such as eltrombopag and transplant strategies that use unrelated and half-matched related donors, are now being studied as options to replace traditional IST. Critical Problem: The advent of new aAA therapies associated with quite different risks and response rates creates a significant dilemma for patients faced with deciding which therapy is best for their specific disease. To assist patients with these therapy decisions, what is critically needed is identification of the factors present at the time of aAA diagnosis that can reliably predict how patients will respond to IST, so that patients who are likely to have good responses to IST receive different treatment versus those at high risk for IST failure or MDS. Preliminary Studies/Hypothesis: We hypothesize that inheritance of specific human leukocyte antigens (HLA), molecules that initiate autoimmune responses in aAA by promoting T cell activation and growth, may increase the risk of IST treatment failure and MDS in patients who have these unique HLA profiles. This hypothesis comes from our preliminary studies of patients enrolled in our Children’s Hospital of Philadelphia/University of Pennsylvania Bone Marrow Failure Patient Registry and Sample Repository. We have found that 15-20% of patients with aAA develop genetic changes in the gene copies (called alleles) that encode these specific HLA molecules. These genetic changes, which we have termed “risk alleles,” result in the inability of bone marrow cells to produce these specific HLA molecules. Bone marrow cells that no longer make these HLA cannot be destroyed by aAA-causing T cells that need these HLA as targets. Thus, specific HLA gene alleles must play important roles in how aAA progresses. Among many hundreds of HLA alleles that are known, we have now identified four specific HLA risk alleles in patients with aAA. In our institutional studies, patients who possess any of these four alleles are more likely to fail IST and progress to clonal diseases, including MDS. Objectives/Aims: The goal of our Bone Marrow Failure Research Program Idea Development Award application is to identify genetic changes that target HLA gene alleles in a large North American multi-center and ethnically diverse aAA cohort. We anticipate our results will confirm that identified HLA risk alleles can serve as prognostic markers to help develop patient-specific approaches to therapy selection and disease monitoring in aAA. In Aim 1, we will use cutting edge genomic technologies to define the true landscape of HLA gene alleles, targeted by the genetic changes discussed above, that convey a high risk of IST failure and MDS development in aAA patient samples derived from the North American Pediatric Aplastic Anemia Consortium (NAPAAC). In Aim 2, we will use these HLA gene alleles, along with state-of-the-art protein and T cell gene profiling technologies, to identify the T cells specifically responsible for causing aAA in patients with HLA risk alleles. We will then create a biobank of these T cells to
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810111
Entities
People
- Timothy M. Olson
Organizations
- United States Army