The thymus is the primary site of T cell development, involuting into fatty tissue in adults. Thymic function persists in the adulthood and may be boosted in certain circumstances. We questioned whether heart transplantation (HTx) was such a clinical situation and whether the thymic function was related to the onset of rejection.

Methods: HTx patients (n=28) received an induction therapy of antithymocyte globulin followed by maintenance immunosuppression. An allograft rejection event was defined as either acute cellular rejection (ACR) grade 2R or higher (n=5) or acute antibody-mediated rejection (AMR) as a pathological AMR2 or higher (n=6) (ISHLT guidelines). Analysis of peripheral blood mononuclear cells of HTx patients was performed by flow cytometry. Intrathymic proliferation of precursor T cells was evaluated through measurement of the sj/βTREC ratio. The effect of thymectomy was tested on the alloimmune humoral response in a rat model of aortic allograft (AA).

Results: A lower proportion of circulating CD4+ and CD8+ T cells with a recent thymic emigrant (RTE) phenotype (CD45RA+ CD62L+ CD31+) was observed in HTx patients than in non-HTx subjects. Strikingly, among HTx patients, AMR patients had a higher proportion of CD4+ RTE cells (p<0.01 vs no rejection and p<0.05 vs ACR). The percentage of CD4+ RTE cells was positively correlated with the sj/β TREC ratio and because we found no difference in IL-15 plasma levels between the different groups of HTx patients, we suggest that they have a thymic origin rather than resulting from homeostatic proliferation. Altogether, these results indicated that a better thymic function might predispose HTx patients for AMR. This hypothesis was supported by experimental data obtained in the AA model where we found a significant positive correlation between RTE CD4+ T cells (%) and DSA level. Remarkably, rats developed significantly less DSA and had lower levels of IL-4, IL-5, and IL-17A if they were thymectomized before the AA.

Conclusion: Our study strongly suggests that thymic function is a major determinant of AMR onset in HTx patients and that thymectomy might be a prophylactic strategy to prevent alloimmune humoral responses and/or to dampen established alloimmune humoral responses.

CITATION INFORMATION: Sannier A, Dorent R, Le Borgne M, Stroumza N, Senemaud J, Louedec L, Andreata F, Gaston A, Deschildre C, Nataf P, Couvelard A, Caligiuri G, Nicoletti A. Is Thymic Function Determining Rejection Onset in Heart Transplantation? Am J Transplant. 2017;17 (suppl 3).

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