A B cell-dependent pathway drives chronic lung allograft rejection after ischemia-reperfusion injury in mice.

Chronic lung allograft dysfunction (CLAD) limits long-term survival after lung transplant (LT). Ischemia-reperfusion injury (IRI) promotes chronic rejection (CR) and CLAD, but the underlying mechanisms are not well understood. To examine mechanisms linking IRI to CR, a mouse orthotopic LT model using a minor alloantigen strain mismatch (C57BL/10 [B10, H-2b ] → C57BL/6 [B6, H-2b ]) and isograft controls (B6→B6) was used with antecedent minimal or prolonged graft storage. The latter resulted in IRI with subsequent airway and parenchymal fibrosis in prolonged storage allografts but not isografts. This pattern of CR after IRI was associated with the formation of B cell-rich tertiary lymphoid organs within the grafts and circulating autoantibodies. These processes were attenuated by B cell depletion, despite preservation of allograft T cell content. Our observations suggest that IRI may promote B cell recruitment that drives CR after LT. These observations have implications for the mechanisms leading to CLAD after LT.

Intragraft regulatory T cells in the modern era: what can high-dimensional methods tell us about pathways to allograft acceptance?

Replacement of diseased organs with transplanted healthy donor ones remains the best and often only treatment option for end-stage organ disease. Immunosuppressants have decreased the incidence of acute rejection, but long-term survival remains limited. The broad action of current immunosuppressive drugs results in global immune impairment, increasing the risk of cancer and infections. Hence, achievement of allograft tolerance, in which graft function is maintained in the absence of global immunosuppression, has long been the aim of transplant clinicians and scientists. Regulatory T cells (Treg) are a specialized subset of immune cells that control a diverse array of immune responses, can prevent allograft rejection in animals, and have recently been explored in early phase clinical trials as an adoptive cellular therapy in transplant recipients. It has been established that allograft residency by Tregs can promote graft acceptance, but whether intragraft Treg functional diversification and spatial organization contribute to this process is largely unknown. In this review, we will explore what is known regarding the properties of intragraft Tregs during allograft acceptance and rejection. We will summarize recent advances in understanding Treg tissue residency through spatial, transcriptomic and high-dimensional cytometric methods in both animal and human studies. Our discussion will explore properties of intragraft Tregs in mediating operational tolerance to commonly transplanted solid organs. Finally, given recent developments in Treg cellular therapy, we will review emerging knowledge of whether and how these adoptively transferred cells enter allografts in humans. An understanding of the properties of intragraft Tregs will help lay the foundation for future therapies that will promote immune tolerance.