Necrotizing enterocolitis (NEC) continues to cause significant mortality and morbidity in premature infants. Despite advances during the past two decades in the other diseases of low birth weight infants, the incidence of NEC is largely unchanged. A major obstacle in its prevention is in the understanding the mechanism of disease and attenuating factors in NEC. Intestinal mucosal damage from ischemia/reperfusion injury (I/R) is one proposed mechanism in the development of NEC. The bowel lumen is colonized with pathogenic organisms shortly after birth and mucosal damage allows translocation of bacteria and toxins from the intestinal lumen, resulting in a pro-inflammatory cascade. Intact and functional adaptive immunity may be critical in preventing entry of these agents and the progression of injury. The premature human infant's ability to respond to specific antigens is much less than term infants. This relative immunodeficiency may in part explain why the incidence of NEC is higher with increasing prematurity. The specific contribution of lymphocytes to mucosal immunity in I/R injury is not well understood. We hypothesize that mature mucosal immunity is necessary for protection from I/R intestinal injury. To test this hypothesis, a murine model of I/R intestinal injury will be used. The first specific aim will be to compare innate immunity activation and I/R injury between wild-type (WT) mice, a severely immunodeficient strain (RAG1) which lack mature B and T cells, and RAG1 mice reconstituted with WT bone marrow stem cells. In addition, the role of restricting the B and T cell repertoire, similar to that of extremely premature infants, in attenuating I/R injury will be studied. The second specific aim involves reconstitution of RAG1 mice with either B or T lymphocyte precursor cells. This arm of the study analyzes of the individual role of B and T cells in I/R injury attenuation. The third specific aim will focus on the role of innate immunity in the mechanism of injury. Separate experiments dissect the specific role of neutrophils, natural killer cells, and toll-like receptor signaling in the model of I/R intestinal injury. The identification and elucidation of the role of adaptive mucosal immunity in acute intestinal injury could clarify the protective mechanisms in NEC as well as provide potential avenues of preventive or therapeutic intervention. ? ? ?
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