Coordinated circulating and tissue-based T cell responses precede xenograft rejection.

Area of Science:

• Immunology
• Transplantation Science
• Xenotransplantation Research

Background:

• Solid organ transplantation faces organ shortages, driving interest in xenotransplantation.
• Porcine xenotransplantation offers a potential solution, but human immune rejection is a significant hurdle.
• Understanding T cell-mediated rejection is crucial for xenograft survival.

Purpose of the Study:

• To investigate T cell responses and repertoire dynamics in a porcine thymokidney xenograft model in humans.
• To identify key T cell populations and their behavior during xenograft rejection.
• To explore potential biomarkers for early detection and intervention in xenograft rejection.

Main Methods:

• Porcine thymokidney transplantation in a decedent model.
• Longitudinal analysis of T cell clonotypes in xenograft biopsies, circulation, and lymph nodes.
• Immune suppression protocols including anti-thymocyte globulin, rituximab, corticosteroids, calcineurin inhibition, and mycophenolate mofetil.
• Mixed lymphocyte reaction to identify donor-reactive T cell clonotypes.

Main Results:

• Human T cell infiltration and xenograft dysfunction were observed despite immunosuppression.
• Accumulation of clonal CD4 and CD8 T cell responses within the thymokidney.
• Xeno-reactive T cells, including circulating T follicular helper cells (cTfh), increased around rejection events.
• A dominant CD8 T cell clonotype, reactive to the donor, was identified preceding acute cellular rejection.
• Treatment modulated T cell clonotype frequencies but did not eliminate them.
• Shared T cell clonotypes across multiple compartments indicated a coordinated immune response.

Conclusions:

• T cell repertoire dynamics play a critical role in porcine xenograft rejection.
• Xeno-reactive T cells are detectable in circulation and infiltrate the xenograft.
• Early surveillance and prediction of rejection are possible through monitoring T cell responses.
• Targeting specific T cell responses may offer therapeutic intervention strategies for xenotransplantation.