Lung transplant acceptance is facilitated by early events in the graft and is associated with lymphoid neogenesis

Abstract

Early immune responses are important in shaping long-term outcomes of human lung transplants. To examine the role of early immune responses in lung rejection and acceptance we developed a method to retransplant mouse lungs. Retransplantation into T cell-deficient hosts showed that for lungs and hearts alloimmune responses occurring within 72 hours of transplantation are reversible. In contrast to hearts, a 72-hour period of immunosuppression with costimulation blockade in primary allogeneic recipients suffices to prevent rejection of lungs upon retransplantation into untreated allogeneic hosts. Long-term lung acceptance is associated with induction of bronchus-associated lymphoid tissue, where Foxp3+ cells accumulate and recipient T cells interact with CD11c+ dendritic cells. Acceptance of retransplanted lung allografts is abrogated by treatment of immunosuppressed primary recipients with anti-CD25 antibodies. Thus, events contributing to lung transplant acceptance are established early in the graft and induction of bronchus-associated lymphoid tissue can be associated with an immune quiescent state.

Central memory CD8+ T lymphocytes mediate lung allograft acceptance

“…address this issue, we transplanted BALB/c lungs into allogeneic athymic nude mice and determined that, in contrast to wild-type recipients (29), these grafts remain ventilated, with little inflammation 1 week after transplantation ( Figure 1A) and long term (30). We have shown previously that, unlike the case for cardiac transplants, lung allografts can be rejected in the absence of CD4 + T cells (31).…”

An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome

“…Advances in understanding the effects of allograft cellular senescence (accelerated ageing) on allograft function and BOS risk are needed, and a better understanding of the role of interleukin-17 [150][151][152][153][154][155][156], autoimmune pathways, regulatory lymphocyte populations [157][158][159][160][161][162][163] and neutrophil responses, as well as mechanisms by which the hypothetical phenomenon of epithelial-mesenchymal transition (which remains hypothetical and has not been well validated in humans) [164][165][166][167] leads to airway fibrosis, may lead to novel therapies to prevent and treat BOS. Improved animal models of OB are needed and are likely to be useful in improving our understanding of the role of these and other phenomena in the initiation, progression, prevention and treatment of OB following lung transplantation.…”

Bidirectional alloreactivity

“…The classical study of Graca et al 58 showing that tissue resident Tregs in tolerated skin grafts were able to prolong survival of retransplanted allografts onto naïve hosts has recently been replicated in a model of orthotopic lung transplantation in mice. 59 The capacity to harbor T reg-enriched organized lymphoid structures (TOLS) in kidney allografts cited previously 39 may be shared with other epithelial tissues such as skin and lung, but not heart. 59 Whether the same principle of Treg-passenger cells applies to bidirectional regulation in living related kidney transplants remains to be proven.…”

“…59 The capacity to harbor T reg-enriched organized lymphoid structures (TOLS) in kidney allografts cited previously 39 may be shared with other epithelial tissues such as skin and lung, but not heart. 59 Whether the same principle of Treg-passenger cells applies to bidirectional regulation in living related kidney transplants remains to be proven.…”