Lymphoid Neogenesis in Allografts: Bad, Good or Neither?
CITATION Baddoura FK, Nasr IW, Wrobel B, Li Q, Ruddle NH, Lakkis FG. Lymphoid neogenesis in murine cardiac allografts undergoing chronic rejection. Am J Transplant 2005; 5:510–516.
CITATION Brown K, Sacks SH, Wong W. Tertiary lymphoid organs in renal allografts can be associated with donor-specific tolerance rather than rejection. Eur J Immunol 2011; 41:89–96.
CITATION Li W, Bribriesco AC, Nava RG, Brescia AA, Ibricevic A, Spahn JH, et al. Lung transplant acceptance is facilitated by early events in the graft and is associated with lymphoid neogenesis. Mucosal Immunol 2012; 5:544–554.
CITATION Nasr IW, Reel M, Oberbarnscheidt MH, Mounzer RH, Baddoura FK, Ruddle NH, Lakkis FG. Tertiary lymphoid tissues generate effector and memory T cells that lead to allograft rejection. Am J Transplant 2007; 7:1071–1079.
CITATION Thaunat O, Field AC, Dai J, Louedec L, Patey N, Bloch MF, et al. Lymphoid neogenesis in chronic rejection: evidence for a local humoral alloimmune response. Proc Natl Acad Sci U S A 2005; 102:14723–14728.
CITATION Zhang N, Schröppel B, Lal G, Jakubzick C, Mao X, Chen D, et al. Regulatory T cells sequentially migrate from inflamed tissues to draining lymph nodes to suppress the alloimmune response. Immunity 2009; 30:458–469.
SUMMARY AND ANALYSIS
The term tertiary lymphoid organ (TLO) refers to the neogenesis of organized lymphoid accumulations at ectopic nonlymphoid sites. They are composed of organized T and B cell zones, have germinal centers, express homeostatic chemokines, contain high endothelial venules (HEVs), which facilitate the extravasation of lymphocytes, and have newly formed lymphatic vessels at the periphery. Lymphoid neogenesis is observed at chronic inflammatory sites, where it is stimulated by the presence of antigens. Examples include lungs affected by chronic obstructive pulmonary disease and allografts, where it has been proposed to contribute to alloimmunity and chronic rejection (Figure 1). Thaunat et al observed tertiary TLOs in rat aortic transplants that produced alloantibodies directed against donor MHC class I, raising the possibility that this tissue mounts a local humoral response. Similarly, Lakkis's group demonstratedT cell priming within graft-resident TLOs that triggered skin allograft rejection (Nasr et al), and correlated TLOs in murine heart allografts with chronic rejection (Baddoura et al). These findings suggest that targeting TLO could represent a novel therapeutic strategy.
However, recent reports have challenged the view that lymphoid neogenesis is necessarily associated with poor outcomes. Brown and coworkers observed TLOs in spontaneously accepting mouse kidneys. Interestingly, a larger mean area and the presence of peripheral nodal addressin-expressing HEV, which is important for the lymphocyte entry, were associated with improved graft function. Furthermore, immunostaining of the TLOs provided evidence that donor alloantigen is presented via both direct and indirect pathways. Li et al reported that bronchus-associated lymphoid tissue is induced during costimulation blockade-mediated long-term acceptance of mouse lung allografts. Intravital two-photon imaging revealed clusters of CD 1 1c+ dendritic cells, which were very motile, displaying probing behavior and interacting extensively with recipient T cells. The majority of T cells within accepted lung grafts were located within this induced bronchus-associated lymphoid tissue and, notably, a large portion of these T cells expressed Foxp3, consistent with a regulatory phenotype. Vessels within the bronchus-associated lymphoid tissue had a distinct appearance compared with the remainder of the allograft and morphologically resembled vessels within peripheral lymph nodes. These observations raise the possibility that TLO may be protective. This may be not entirely surprising as recent studies have shown that secondary lymphoid organs (SLOs) are also critical to downregu-late immune responses to allografts (Zhang et al). Thus trafficking of regulatory T cells from allografts to draining lymph nodes is an essential step in mediating their activation and full suppressive function, and an allograft TLO may be a site of local immunoregulation.
Intragraft TLOs provide a local structural environment where recipient lymphocytes can extravasate and encounter donor alloantigen for the life of the graft. An important caveat of the above-referenced studies is their correlative nature. Future studies will need to determine whether alloimmune responses within allograft TLOs differ from those generated within the recipient's SLOs. Ongoing efforts to elucidate pathways that lead to the development and maintenance of TLOs within allografts will potentially enable investigators to prevent their neogenesis or disrupt them and thereby more directly test whether and how they regulate the fate of grafts.
Dr. Kreisel is Associate Professor of Surgery, Pathology and Immunity, Washington University, St. Louis. Dr. Bromberg is professor of Surgery and Microbiology and Immunology, and is the chief of the Division of Transplantation, University of Maryland Medical Center, Baltimore. He is also section editor for “Literature Watch.”