The purpose of this IRB-approved study is to determine if there is a potential role for CD8⁺ T cell-mediated suppression of donor specific alloantibody (DSA) production in human kidney transplant (Tx) recipients. Our group is the first to report a novel subset of antibody-suppressing IFN-g⁺CD8⁺ T cells that inhibit DSA production by killing B cells and downregulating CD4⁺ T cell expression of IL-4 and IL-21. Therefore, we hypothesized that human Tx recipients, who are at risk for developing DSA, may be identified by the relative frequency of Th1/Th2 cytokine-expressing CD4⁺ T cells and IFN-g⁺CD8⁺ T cells. Results: Our studies aimed to prospectively correlate the number of CD4⁺ and CD8⁺ T cells expressing select cytokine profiles to the occurrence of de novo postTx DSA production. When comparing the peripheral blood immune profiles of kidney Tx patients, we observed two groups- Group 1) those who have not developed de novo DSA (n=23, mean follow-up 8 months) and Group 2) those Tx patients who developed de novo DSA (n=7, mean follow-up 10.2 months). By prospectively collecting peripheral blood lymphocytes overtime (preTx and 1,3,6,9,12 months postTx), we are able to evaluate the immune profiles of Tx patients relative to the development of de novo DSA. In Group 2, we noted in studies that 2.9±0.7 months prior to the development of DSA, these recipients exhibited distinct immune profiles in which there was a 2-fold greater number of peripheral Th2 IL-4⁺CD4⁺ T cells (16.2±2.2 x10³ vs 6.9±1.2 x10³ cells/10⁶ PBMCs) and 4-fold greater number of Th1 IFN-g⁺CD4⁺ T cells (14.6±3.1 x10³ vs 3.6±1.6 x10³ cells/10⁶ PBMCs) compared to Group 1. Patients in Group 1 have a 2-fold greater number of IFN-g⁺CD8⁺ T cells (antibody-suppressor phenotype; 15.1±2.2 x10³ cells/10⁶ PBMCs) than patients in Group 2 (8.2±4.7 x10³). When analyzing ratios of IFN-g⁺CD8⁺ T cells to cytokine-positive CD4⁺ T cells, we observe a 4-fold lower ratio of peripheral IFN-g⁺CD8⁺ T cells to IL-4⁺CD4⁺ T cells (ratio=0.6 vs 2.1) in Group 2 compared to Group 1. Likewise, we find a 7-fold lower ratio of peripheral IFN-g⁺CD8⁺ T cells to IFN-g⁺CD4⁺ T cells (ratio=0.6 vs 4.2) in Group 2 compared to Group 1. Altogether our data is supportive of a CD8-mediated DSA suppressor mechanism in human kidney Tx recipients, similar to the mechanism uncovered in rodent studies. However, longer-term follow up and more study participants and additional studies are needed to extend these early results.

CITATION INFORMATION: Zimmerer J, Ringwald B, Pelletier R, El-Hinnawi A, Rajab A, Bumgardner G. Early Results of Immune Profile Emerging Before Detection of De Novo Humoral Alloimmunity in Kidney Transplant Recipients. Am J Transplant. 2017;17 (suppl 3).

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