A. A high risk of acute cellular rejection (ACR) is one of the key factors limiting intestinal transplantation (ITx). An extremely poor prognosis is related to severe exfoliative allograft rejection. The current therapy for severe ACR is with anti-thymocyte globulin (ATG) depletion therapy. The purpose of this study was to delineate the underlying mechanisms of depletion therapy resistant ACR in ITx patients.

B. To precisely study the mechanism of depletion resistant allograft rejection we analyzed blood and intestinal biopsy samples obtained from a cohort of ITx patients with histologically confirmed severe ACR. Phenotype and effector functions of pro-inflammatory allograft mediating T cells were further characterized by immunohistochemistry (IHC) and polychromatic flow cytometry.

C. First, we studied peripheral blood CD3+ levels in patients receiving ATG and found that all patients were equally depleted despite a varied clinical response to ATG, suggesting that peripheral blood monitoring does not accurately detect the intestinal response to therapy. Based on this we hypothesized that pro-inflammatory T cell clones in the allograft mediate severe ACR and resistance to depletion therapy. To test this hypothesis, we studied samples pre, peri and post thymoglobulin treatment using IHC and flow cytometry. To our surprise we found a subset of patients did not deplete T cells in ITx despite full depletion in peripheral blood, indicating that persistent intestinal T cells drive ATG resistant allograft rejection. Critically, immunologic analysis revealed the depletion resistant clones to be effector memory T cells in patients with ATG resistant ACR. Importantly, a positive correlation was found between the level of intestinal T cell depletion in response to ATG and pathology proven resolution of ACR suggesting that real time immunomonitoring of the ITx allograft during depletion therapy can determine immunological responsiveness to treatment and allow for a focused tailoring of therapy.

D. In summary, our study indicates that there is a subset of ITx patients with severe ACR who despite depletion of peripheral T cells retain depletion resistant effector memory T cells in their allograft. Immunomonitoring of intestinal T cell depletion during therapy may allow for a more precise measure of therapeutic response.

CITATION INFORMATION: Cosentino C, Kaiser J, Shukla A, Desai C, Girlanda R, Hawksworth J, Matsumoto C, Zasloff M, Fishbein T, Kroemer A. CD45RO+/CD62L- Effector Memory T Cells Mediate Depletion Resistant Allograft Rejection in Intestinal Transplant Recipients. Am J Transplant. 2016;16 (suppl 3).

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