T-cell epitopes shared between immunizing HLA and donor HLA associate with graft failure after kidney transplantation

Peereboom, E.T.M.; Matern, B.M.; Tomosugi, T.; Niemann, M.; Drylewicz, J.; Joosten, I.; Allebes, W.A.; Meer, A. van der; Hilbrands, L.B.; Baas, M.C.; Reekum, F.E. van; Verhaar, M.C.; Kamburova, E.G.; Seelen, M.A.J.; Sanders, J.S.; Hepkema, B.G.; Lambeck, A.J.; Bungener, L.B.; Roozendaal, C.; Tilanus, M.G.J.; Voorter, C.E.; Wieten, L.; Duijnhoven, E.M. van; Gelens, M.A.C.J.; Christiaans, M.H.L.; Ittersum, F.J. van; Nurmohamed, A.; Lardy, N.M.; Swelsen, W.; Pant, K.A. van der; Weerd, N.C. van der; Berge, I.J.M. ten; Bemelman, F.J.; Vries, A.P.J. de; Fijter, J.W. de; Betjes, M.G.H.; Roelen, D.L.; Claas, F.H.; Otten, H.G.; Heidt, S.; Zuilen, A.D. van; Kobayashi, T.; Geneugelijk, K.; Spierings, E.

doi:doi:10.3389/fimmu.2021.784040

CD4(+) T-helper cells play an important role in alloimmune reactions following transplantation by stimulating humoral as well as cellular responses, which might lead to failure of the allograft. CD4(+) memory T-helper cells from a previous immunizing event can potentially be reactivated by exposure to HLA mismatches that share T-cell epitopes with the initial immunizing HLA. Consequently, reactivity of CD4(+) memory T-helper cells toward T-cell epitopes that are shared between immunizing HLA and donor HLA could increase the risk of alloimmunity following transplantation, thus affecting transplant outcome. In this study, the amount of T-cell epitopes shared between immunizing and donor HLA was used as a surrogate marker to evaluate the effect of donor-reactive CD4(+) memory T-helper cells on the 10-year risk of death-censored kidney graft failure in 190 donor/recipient combinations using the PIRCHE-II algorithm. The T-cell epitopes of the initial theoretical immunizing HLA and the...Show moreCD4(+) T-helper cells play an important role in alloimmune reactions following transplantation by stimulating humoral as well as cellular responses, which might lead to failure of the allograft. CD4(+) memory T-helper cells from a previous immunizing event can potentially be reactivated by exposure to HLA mismatches that share T-cell epitopes with the initial immunizing HLA. Consequently, reactivity of CD4(+) memory T-helper cells toward T-cell epitopes that are shared between immunizing HLA and donor HLA could increase the risk of alloimmunity following transplantation, thus affecting transplant outcome. In this study, the amount of T-cell epitopes shared between immunizing and donor HLA was used as a surrogate marker to evaluate the effect of donor-reactive CD4(+) memory T-helper cells on the 10-year risk of death-censored kidney graft failure in 190 donor/recipient combinations using the PIRCHE-II algorithm. The T-cell epitopes of the initial theoretical immunizing HLA and the donor HLA were estimated and the number of shared PIRCHE-II epitopes was calculated. We show that the natural logarithm-transformed PIRCHE-II overlap score, or Shared T-cell EPitopes (STEP) score, significantly associates with the 10-year risk of death-censored kidney graft failure, suggesting that the presence of pre-transplant donor-reactive CD4(+) memory T-helper cells might be a strong indicator for the risk of graft failure following kidney transplantation.Show less

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T-cell epitopes shared between immunizing HLA and donor HLA associate with graft failure after kidney transplantation