The Role of Lymphoid Neogenesis in Allografts

Abstract

De novo induction of organized lymphoid aggregates at non-lymphoid sites has been observed in many chronic inflammatory conditions where foreign antigens such as infectious agents, auto- or alloantigens, persist. The prevailing opinion in the field of transplantation is that lymphoid neogenesis within allografts is detrimental to the establishment of immune tolerance. These structures, commonly referred to as tertiary lymphoid organs (TLOs), are thought to contribute to graft rejection by generating and propagating local alloimmune responses. However, recent studies have shown that TLOs rich in regulatory Foxp3+ cells are present in long term accepting allografts. The notion that TLOs can contribute to the local downregulation of immune responses has been corroborated in other chronic inflammation models. These findings suggest that contrary to previous suggestions that the induction of TLOs in allografts is necessarily harmful, the induction of “tolerogenic” TLOs may prove advantageous. In this review, we discuss our current understanding of how TLOs are induced and how they regulate immune responses with a particular focus on alloimmunity.

IL-22 is required for the induction of bronchus-associated lymphoid tissue in tolerant lung allografts

“…TLOs that are induced in transplanted grafts have been mostly associated with deleterious immune responses . For example, TLOs have been observed in cardiac allografts that have evidence of acute or chronic rejection .…”

Bronchus-associated lymphoid tissue–resident Foxp3+ T lymphocytes prevent antibody-mediated lung rejection

“…Of note, the existence of bystander regulation has raised concerns about the potential to compromise immunity to pathogens in transplant recipients, where tolerance is induced (15). It has been the prevailing notion that the induction of tertiary lymphoid organs in allografts results in locally generated deleterious immune responses (16,17). These structures have been observed in murine and human cardiac allografts that undergo either acute or chronic rejection (18,19).…”

Report of the ISHLT Working Group on Primary Lung Graft Dysfunction Part III: Mechanisms: A 2016 Consensus Group Statement of the International Society for Heart and Lung Transplantation

“…64,65 That function has been ascribed to inhibiting antigen-dependent responses, including experimental studies of immunosuppression-mediated lung transplant tolerance. 66–68 However, Tregs also have been reported to resolve experimental acute lung injury by inhibiting macrophage pro-inflammatory responses through augmenting neutrophil efferocytosis. 69 Moreover, they have been shown to limit fibroproliferation and augment alveolar epithelial repair.…”