IL-17–dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants

Abstract

Bronchiolitis obliterans syndrome (BOS), a process of fibro-obliterative occlusion of the small airways in the transplanted lung, is the most common cause of lung transplant failure. We tested the role of cell-mediated immunity to collagen type V [col(V)] in this process. PBMC responses to col(II) and col(V) were monitored prospectively over a 7-year period. PBMCs from lung transplant recipients, but not from healthy controls or col(IV)-reactive Goodpasture's syndrome patients after renal transplant, were frequently col(V) reactive. Col(V)-specific responses were dependent on both CD4+ T cells and monocytes and required both IL-17 and the monokines TNF-alpha and IL-1beta. Strong col(V)-specific responses were associated with substantially increased incidence and severity of BOS. Incidences of acute rejection, HLA-DR mismatched transplants, and induction of HLA-specific antibodies in the transplant recipient were not as strongly associated with a risk of BOS. These data suggest that while alloimmunity initiates lung transplant rejection, de novo autoimmunity mediated by col(V)-specific Th17 cells and monocyte/macrophage accessory cells ultimately causes progressive airway obliteration.

High-mobility group box 1 promotes early acute allograft rejection by enhancing IL-6-dependent Th17 alloreactive response

“…34 Moreover, pretransplant patients who show collagen (V) reactivity have an increased incidence of early graft dysfunction following transplantation. 35 Most recently, two groups have shown that a highly purified population of Th17 cells is capable of inducing lethal GVHD, hallmarked by extensive pathologic cutaneous and pulmonary lesions.…”

Overview of Clinical Lung Transplantation

“…Autoimmune processes have also been shown to play a role. Exposure of typically cryptic antigens such as type-V collagen and K-a1 tubulin during the lung transplant process may help drive the CLAD process (Burlingham et al 2007;Goers et al 2008).…”

Comprehensive Mass Spectrometric Mapping of the Hydroxylated Amino Acid residues of the α1(V) Collagen Chain

“…Thus, mutations in the genes encoding either ␣1(V) or ␣2(V) chains result in the human connective tissue disorder classic Ehlers-Danlos syndrome, characterized by collagen I fibrils of abnormal shapes and diameters and deficient tensile strength (7,8). More recently, it has been demonstrated that anti-col(V) autoimmune responses can underlie chronic lung transplant rejection in both humans (9) and animal models (10) and that pre-transplant col(V)-specific autoimmunity is also a significant risk factor for primary graft dysfunction, the leading cause of early morbidity and mortality after lung transplantation (11,12). Col(V) autoimmunity has also been identified as a consistent feature in both late stage human coronary artery disease and a mouse model of atherosclerosis (13).…”