We recently generated transgenic mice in the autoimmunity-prone nonobese diabetic (NOD) background to target CD5, a regulator of T and B lymphocyte activity, using inducible RNAi. We discovered that the loss of CD5 in NOD mice caused severe wasting disease. Histological examination revealed widespread gastrointestinal inflammation, with pathology resembling Crohn's disease lesions. Critically, reinstating CD5 after clinical manifestation reversed the course of disease and prevented otherwise fatal weight loss. Most animal models of inflammatory bowel disease (IBD) are characterized by colitis and replicate features of human ulcerative colitis. A handful of IBD models affect the ileum, and these are more representative of Crohn's disease that can affect any region of the gastrointestinal tract. The new model we have generated in our laboratory is unique, because inflammation spreads from the stomach through the small intestine to the colon. CD5 knockdown NOD mice thus constitute perhaps the only available IBD model for Crohn's disease that reproduces the widespread inflammation found in patients. This feature is significant, as this unique model may yield better insight into human disease. The overall objective of this proposal is to understand the mechanism by which CD5 controls the pathological immune activity that underlies inflammatory bowel disease (IBD) in NOD mice. In particular, we seek to determine how restoring CD5 regulation is capable of halting immunopathology and of curing diseased animals. We anticipate that understanding this novel regulatory mechanism will have significant implications for the therapy of human IBD. Because CD5 is expressed on all T cell and on a subset of B cells, we will initially take a broad approach to determine in which exact cell population CD5 exerts its regulation of gastrointestinal immunity. Using both genetic and pharmacological manipulations, we will define the respective role of different lymphocyte subpopulations in disease pathogenesis and regulation. We will then characterize in more detail the mechanism by which CD5 controls disease. The ability of CD5 to halt ongoing IBD when gene expression is restored indicates that CD5 has a dominant regulatory function over the immune activity that causes gastrointestinal inflammation. We anticipate that defining the exact mechanism that allows CD5 to restrain IBD in NOD mice may lead to new strategies for the treatment of Crohn's disease.

Public Health Relevance

CD5 is widely expressed in the lymphocytic compartment, and while a role in modifying lymphocyte reactivity has been established, its function in immune regulation remains ill-defined. We recently discovered that the loss of CD5 in autoimmune-prone nonobese diabetic (NOD) mice causes severe gastrointestinal inflammation resembling Crohn's disease. We now aim to understand the mechanism by which CD5 critically regulates gastrointestinal immunity, with the prospect of developing new therapeutic strategies for inflammatory bowel disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
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Rothermel, Annette L
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Joslin Diabetes Center
United States
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