A. This study aimed to determine the mechanisms underlying T cell depletion-resistant moderate to severe acute cellular rejection (ACR) in intestinal transplantation (ITx) patients.

B. A cohort of 31 out of a total 249 ITx patients who were treated with Thymoglobulin (Thy) for histologically confirmed Grade II to III ACR was identified from the Georgetown Transplant Institute Tissue Bank Study. Immunomonitoring was accomplished by immunohistochemistry (IHC) and polychromatic flow cytometry (PFC). Clinical non-responders, 15 of the 31, were defined as patients with ongoing rejection while refractory to treatment or re-rejection within 90 days.

C. Serial histological analysis of peripheral blood was performed on the 16 clinical responders and 15 non-responders. Surprisingly, peripheral CD3 populations uniformly depleted in both responders and non-responders (2.12% vs. 2.82%, p=0.673). This indicated that monitoring CD3 in peripheral blood is not reliable and fails to correlate with treatment responsiveness. Thus, we hypothesized that Thy-resistant allograft rejection is driven by depletion resistant T cells in the allograft itself. Longitudinal IHC analysis of rejecting allografts confirmed that the degree of T cell depletion in the allograft correlated with clinical responsiveness. Specifically, 70% T cell depletion was found in responders to Thy treatment versus only 40% in non-responders (p<0.03). Next, to precisely characterize the depletion resistant cell phenotypes in the allograft, patients with ongoing severe ACR were prospectively immunomonitored with PFC. The vast majority of all depletion resistant CD4⁺and CD8⁺ cell populations demonstrated more than 90% presence of CD62L^–CD45RO⁺ effector memory T cell (TEM) and/or CD62L^–CD45RO^– terminally differentiated effector memory T cell (TEMRA) phenotypes, which have been previously implicated in other solid organ transplant rejections.

D. This study demonstrates that the immunomonitoring of T cell depletion in the allograft is clinically superior to peripheral blood during treatment of ACR with Thy in human ITx patients. Phenotype analysis suggests that TEMs and TEMRAs are critical effector cells in Thy depletion resistant ACR, which may have implications for the design of novel clinical diagnosis and treatment strategies.

CITATION INFORMATION: Aguirre O., Houlihan B., Karabala A., Cosentino C., Girlanda R., Hawksworth J., Matsumoto C., Zasloff M., Fishbein T., Kroemer A. Depletion Resistant Effector Memory T Cells Mediate Thymoglobulin Refractory Allograft Rejection in Human Intestinal Transplant Recipients Am J Transplant. 2017;17 (suppl 3).

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