CD103 blockade reduces CD8 T cell accumulation during GVHD, but does not attenuate GVL effects
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Series/Report no.:2011 Edward F. Hayes Graduate Research Forum. 25th
Purpose: Every four minutes someone in America is diagnosed with a blood cancer, and the Leukemia & Lymphoma Society estimates that over 50,000 people die of a blood cancer each year1. Many blood cancers are caused by white blood cells that undergo uncontrolled cell division. This uncontrolled replication causes the affected cells to be non-functional. Furthermore, normal white blood cells are crowded out by the malignant cells, leaving the patient highly immunosuppressed. Current therapies for blood cancers include radiation therapy and more than 50 chemotherapy drugs1. However, many of these drugs are ineffectual in treating the disease, thus alternative therapies are desired. Bone marrow transplants represent a curative therapy for patients with blood cancers. Immediately preceding a bone marrow transplant, the patient is treated with drugs and/or radiation to destroy their immune system, thereby killing the cancer cells. The patient is then infused with bone marrow cells from a genetically similar individual. Bone marrow cells are the immune cell precursors, so the bone marrow transplant recipient receives the cancer-free donor immune system. The limiting factor to the broad use of bone marrow transplants as a curative therapy for blood cancers is graft verses host disease (GVHD). GVHD is caused by a mature subset of white blood cells (T cells) present in the bone marrow graft that recognize and destroy host tissue, particularly epithelial cells in the gut. Depletion of mature T cells prior to transplant is not a viable treatment strategy because mature T cells facilitate several beneficial effects that are essential to a successful transplant. These effects include controlling opportunistic infections and preventing cancer relapse. Therefore, the goal of our research is to find a way to separate the T cells that cause GVHD from those that facilitate the beneficial effects post transplant. Integrins are molecules that facilitate adhesion between cells. Integrins present on the surface of T cells help determine where T cells are go and how long they stay in a particular location after transplant. Previous work in our lab has shown that the integrin CD103 is expressed on a subset of T cells called CD8+ T cells2. Our work has shown that CD103 expression on CD8+ T cells promotes the association of CD8+ T cells with epithelial cells3. We hypothesize that CD103 will be required for the retention of CD8+ T cells in the epithelium of the gut during GVHD, but will not be required for effective clearance of a blood malignancy. Research Methods: To test our hypothesis, we used murine models of GVHD. Mice were irradiated to destroy the host immune system. Recipients were then transplanted with donor bone marrow to restore immune function and donor T cells to cause GVHD. Following the transplant, mice were monitored daily for clinical signs of GVHD. At predetermined time points, groups of mice were sacrificed for further analysis of T cell migration and expression levels of CD103. To test whether CD103 was required for effective clearance of a blood malignancy, a genetically modified mouse was used. The genetically modified mouse has a DNA mutation that causes a subset of white blood cells (B cells) to proliferate uncontrolled. The disease course in this mouse is very similar to the human disease chronic lymphocytic leukemia (CLL). Recipient mice with murine CLL were transplanted with either normal or CD103 deficient T cells, and the ability to eradicate CLL was compared between the two groups. Findings: Using our model of GVHD, we found that mature donor CD8+ T cells accumulate in the gut of mice with GVHD. Interestingly, CD103 expression levels on CD8+ T cells in the gut increased dramatically over time. Concurrent with increased CD103 expression levels, we noticed progressive intestinal injury in our GVHD recipients. Using transgenic mice, we found that CD103 was required for optimal accumulation of CD8+ T cells in the gut, and without CD103 present, we found dramatically fewer CD8+ T cells in the gut. Studies are underway to determine if the progressive intestinal injury is dependent on CD103. Furthermore, CD103 was not required for clearance of malignant B cells. Both normal CD8+ T cells and CD103 knock out CD8+ T cells were able to clear malignant B cells with the same efficiency. Implications: Our data shows that CD103 promotes accumulation of GVHD causing CD8+ T cells in the gut. We show that CD103 expression levels increase over time, concurrent with severe intestinal injury. This finding suggests that CD103 is promoting the retention of CD8+ T cells in the gut and allowing them to cause more damage. Lastly, our data show that CD103 is not required to kill malignant B cells. Taken together, these data provide insight into the potential of altering integrins as a means to separate GVHD from the beneficial properties T cells possess after a bone marrow transplant. Altering integrin expression can potentially decrease T cell retention in GVHD target organs while maintaining the ability to kill residual blood malignancies and lower relapse rates.
Biological Sciences: 1st Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
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