Abstract
Tissue resident lymphocytes are present within many organs, and are presumably transferred at transplantation, but their impact on host immunity is unclear. Here, we examine whether transferred donor natural regulatory CD4 T cells (nT‐regs) inhibit host alloimmunity and prolong allograft survival. Transfer of donor‐strain lymphocytes was first assessed by identifying circulating donor‐derived CD4 T cells in 21 consecutive human lung transplant recipients, with 3 patterns of chimerism apparent: transient, intermediate, and persistent (detectable for up to 6 weeks, 6 months, and beyond 1 year, respectively). The potential for transfer of donor nT‐regs was then confirmed by analysis of leukocyte filters recovered from ex vivo normothermic perfusion circuits of human kidneys retrieved for transplantation. Finally, in a murine model of cardiac allograft vasculopathy, depletion of donor CD4 nT‐regs before organ recovery resulted in markedly accelerated heart allograft rejection and augmented host effector antibody responses. Conversely, adoptive transfer or purified donor‐strain nT‐regs inhibited host humoral immunity and prolonged allograft survival, and more effectively so than following administration of recipient nT‐regs. In summary, following transplantation, passenger donor‐strain nT‐regs can inhibit host adaptive immune responses and prolong allograft survival. Isolated donor‐derived nT‐regs may hold potential as a cellular therapy to improve transplant outcomes.
Highlights
Still considered a novel technology, ex vivo perfusion of recovered organs from deceased donors is likely to become widely adopted in the near future.[1,2] Ex vivo perfusion offers the potential to assess the viability of organs before transplantation, and to ex‐ tend the acceptable period between recovery and implantation
We have recently reported that passenger T cells are present within human donor organs recovered for transplantation and, using murine transplant models, have demonstrated that donor T effec‐ tor cells can augment host alloimmune responses directed against the allograft.[6]
Our previous work has highlighted that chronic allograft vasculopathy (CAV) in this model is associated with the development of effector autoantibody responses that are triggered by graft‐versus‐host recognition of MHC class II on host B cells by passenger donor CD4 T lymphocytes.[6,12,13]
Summary
Still considered a novel technology, ex vivo perfusion of recovered organs from deceased donors is likely to become widely adopted in the near future.[1,2] Ex vivo perfusion offers the potential to assess the viability of organs before transplantation, and to ex‐ tend the acceptable period between recovery and implantation It may enable targeting of the isolated organs with specific thera‐ pies aimed at prolonging allograft survival.[3] One particular focus of such strategies is likely to be donor‐derived T cell populations (naïve or memory) that are resident within the graft.[4,5]. We have recently reported that passenger T cells are present within human donor organs recovered for transplantation and, using murine transplant models, have demonstrated that donor T effec‐ tor cells can augment host alloimmune responses directed against the allograft.[6] seemingly counterintuitive, these pas‐ senger lymphocytes contribute to rejection of the organ. We examine whether donor‐derived natural regulatory CD4 T cells (nT‐ regs) can, prolong allograft survival
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