A.E. Gelman

CCR2 Regulates Monocyte Recruitment As Well As CD4+ Th1 Allorecognition After Lung Transplantation

Graft rejection remains a formidable problem contributing to poor outcomes after lung transplantation. Blocking chemokine pathways have yielded promising results in some organ transplant systems. Previous clinical studies have demonstrated upregulation of CCR2 ligands following lung transplantation. Moreover, lung injury is attenuated in CCR2‐deficient mice in several inflammatory models. In this study, we examined the role of CCR2 in monocyte recruitment and alloimmune responses in a mouse model of vascularized orthotopic lung transplantation. The CCR2 ligand MCP‐1 is upregulated in serum and allografts following lung transplantation. CCR2 is critical for the mobilization of monocytes from the bone marrow into the bloodstream and for the accumulation of CD11c+ cells within lung allografts. A portion of graft‐infiltrating recipient CD11c+ cells expresses both recipient and donor MHC molecules. Two‐photon imaging demonstrates that recipient CD11c+ cells are associated with recipient T cells within the graft. While recipient CCR2 deficiency does not prevent acute lung rejection and is associated with increased graft infiltration by T cells, it significantly reduces CD4+ Th1 indirect and direct allorecognition. Thus, CCR2 may be a potential target to attenuate alloimmune responses after lung transplantation.

Immune Response to Tissue Restricted Self-Antigens Induces Airway Inflammation and Fibrosis Following Murine Lung Transplantation

Immune responses against lung‐associated self‐antigens (self‐Ags) are hypothesized to play a role in the development of chronic lung graft rejection. We determined whether immune responses to lung self‐Ags, K‐alpha‐1‐tubulin (Kα1T) and Collagen V (Col‐V) in the absence of alloimmunity, could promote airway inflammation and fibrosis. Following syngeneic murine orthotopic lung transplantation (LTx) we administered antibodies (Abs) to either Kα1T or Col‐V or in combination to both of these self‐Ags. As compared to recipients of isotype control Abs, Kα1T Abs and/or Col‐V Abs‐treated recipients had marked lung graft cellular infiltration and bronchiolar fibrosis. This inflammation was also associated the accumulation of Kα1T and Col‐V‐specific interferon‐γ+ and IL‐17+ T cells. Notably, the administration of Abs to Kα1T led to cellular and humoral immune responses to Col‐V prior to development of fibrosis, and vice versa, indicating that epitope spreading can occur rapidly in an alloantigen independent manner. Collectively, these data support a model of chronic LTx rejection where the progressive loss of self‐tolerance through epitope spreading promotes airway fibrosis. Strategies that target autoreactive Abs may be useful to inhibit chronic rejection of lung grafts.

The Role of Lymphoid Neogenesis in Allografts.

De novo induction of organized lymphoid aggregates at nonlymphoid sites has been observed in many chronic inflammatory conditions where foreign antigens such as infectious agents, autoantigens 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.

B Cell-Activating Transcription Factor Plays a Critical Role in the Pathogenesis of Anti-Major Histocompatibility Complex-Induced Obliterative Airway Disease.

Antibodies (Abs) against major histocompatibility complex (MHC) results in T helper‐17 (Th17)‐mediated immunity against lung self‐antigens (SAgs), K‐α1 tubulin and collagen V and obliterative airway disease (OAD). Because B cell–activating transcription factor (BATF) controls Th17 and autoimmunity, we proposed that BATF may play a critical role in OAD. Anti‐H2Kb was administered intrabronchially into Batf –/– and C57BL/6 mice. Histopathology of the lungs on days 30 and 45 after Ab administration to Batf –/– mice resulted in decreased cellular infiltration, epithelial metaplasia, fibrosis, and obstruction. There was lack of Abs to SAgs, reduction of Sag‐specific interleukin (IL)‐17 T cells, IL‐6, IL‐23, IL‐17, IL‐1β, fibroblast growth factor‐6, and CXCL12 and decreased Janus kinase 2, signal transducer and activator of transcription 3 (STAT3), and retinoid‐related orphan receptor γT. Further, micro‐RNA (miR)‐301a, a regulator of Th17, was reduced in Batf –/– mice in contrast to upregulation of miR‐301a and downregulation of protein inhibitor of activated STAT3 (PIAS3) in anti‐MHC–induced OAD animals. We also demonstrate an increase in miR‐301a in the bronchoalveolar lavage cells from lung transplant recipients with Abs to human leukocyte antigen. This was accompanied by reduction in PIAS3 mRNA. Therefore, we conclude that BATF plays a critical role in the immune responses to SAgs and pathogenesis of anti‐MHC–induced rejection. Targeting BATF should be considered for preventing chronic rejection after human lung transplantation.

PD-1 expression on CD8+ T cells regulates their differentiation within lung allografts and is critical for tolerance induction

Immunological requirements for rejection and tolerance induction differ between various organs. While memory CD8+ T cells are considered a barrier to immunosuppression‐mediated acceptance of most tissues and organs, tolerance induction after lung transplantation is critically dependent on central memory CD8+ T lymphocytes. Here we demonstrate that costimulation blockade‐mediated tolerance after lung transplantation is dependent on programmed cell death 1 (PD‐1) expression on CD8+ T cells. In the absence of PD‐1 expression, CD8+ T cells form prolonged interactions with graft‐infiltrating CD11c+ cells; their differentiation is skewed towards an effector memory phenotype and grafts are rejected acutely. These findings extend the notion that requirements for tolerance induction after lung transplantation differ from other organs. Thus, immunosuppressive strategies for lung transplant recipients need to be tailored based on the unique immunological properties of this organ.

Activating Killers by Stimulating RAGE

Ischemia–reperfusion injury (IRI) is a common postoperative complication that is a major cause of both shortand longtermmortality in lung recipients. Characterized by poor lung function and the appearance of radiographic infiltrates, currently there is no effective therapy for lung transplantmediated IRI. Over the past two decades, data from experimental models of lung transplantation show that most pulmonary damage is controlled by a macrophage– neutrophil axis. First, respondingmainly to the accumulation of damage-associated molecular patterns (DAMPs), macrophages release reactive oxygen intermediates and inflammatory mediators that stimulate the expression of adhesion molecules and promote the dissolution of endothelial cell tight junctions to initiate inflammatory cell infiltration. Then neutrophils, themost common infiltratingcells in injured lung grafts, release the bulk of proteolytic enzymes that further catalyzethebreakdownofhomeostaticbarriers leadingtothe loss of efficient gas exchange.