We propose a reexamination of the currently underappreciated role of B-1 cells in IRI. Ischemia reperfusion injury (IRI) is a two phase insult composed of an acute, ischemic injury leading to energy depletion and the build-up of oxidative species which, alongside cellular effectors, cause further damage following reperfusion, resumption of blood flow. IRI takes place in a variety of clinical settings but is particularly relevant to transplant recipients since every allograft will experience some degree of IRI. Donor organs are in short supply and extended criteria grafts are both more likely to experience prolonged insult and less able to handle the injury. This leads to increased rates of graft failure and acute and chronic rejection and consequently patient mortality.

B-1 cells are a subset of B lymphocytes different from conventional, B-2 cells, in that they derive from a self-renewing progenitor early in development. They do not undergo N-region addition during V region rearrangement; nor do they undergo somatic hypermutation and thus exhibit a limited repertoire of lower affinity natural antibody(NAb). A common target of NAb are self-antigens associated with apoptotic debris. CD5 expression distinguishes B-1a(+) and B-1b(-) cells. B-1a are not traditionally thought to circulate outside the pleural and peritoneal cavities. We have established a unilateral renal IRI using a basic laparotomy followed by renal pedicle clamping for 60min. In B6 mice, following renal IRI, there is a significant increase in CD5+CD43+ B-1a cells in the tissue by flow cytometry as early as 16hours compared to sham controls (300%, p<0.05). These cells are maintained in the inflamed tissues at least through 72hours. In vitro assays suggest these cells possess many regulatory functions including a significant potential to produce IL-10 in response to BCR signaling; which may be an innate regulator of early inflammation in our model. At 72hours reperfusion, there is an increase in T lymphocytes in the inflamed kidney (250%, p<0.05). Preliminary experiments indicate as much as 15% of the T cell infiltrate is CD4+CD25+, possibly Treg. We propose to examine whether B-1a cells have a regulatory role and if so do they interact with Treg. Understanding how inflammation is regulated following renal ischemia and determining the role of B-1a cells could provide a potential therapeutic for transplant patients.

CITATION INFORMATION: Firl D, Das A, Fung J, Carroll M. Re-Examining the Role of B-1 Cells in a Murine Model of Renal Ischemia Reperfusion Injury. Am J Transplant. 2016;16 (suppl 3).

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