Immune rejection of orthopedic tissue allograft scoping review: Are we missing a cause of graft/procedural failure? Current concepts

Allograft transplants are commonly used in orthopedics. Unlike other transplanted tissues, orthopedic tissue allografts are not human leukocyte antigen (HLA)-matched. The clinical impact of the immune response to allografts is poorly understood. Recent experience with allograft failures and reactions to anterior cruciate ligaments (ACL), medial patellofemoral ligament (MPFL), osteochondral, and meniscus transplants raises concern. This scoping review examines the literature on immunologic rejection of orthopedic tissue allograft using PubMed, Embase, Web of Science, and Scopus for studies describing immune rejection of orthopedic tissue allografts in humans and animals. Four reviewers independently screened titles/abstracts based on these criteria. Full texts were screened independently by two reviewers for inclusion. Variables of interest included the species, graft type, and graft treatment. Our literature search yielded 1625 articles, with 78 meeting the inclusion criteria. Of these studies, 30 (38.5%) were in humans, 16 (20.5%) in rats, and 11 (14.1%) in dogs. The remaining 21 studies were in a combination of rabbit, primate, mice, sheep, and cat subjects. The orthopedic tissues in these studies included 23 osteochondral (29.5%), 16 bone (20.5%), 13 cartilage (16.7%), 6 bone-tendon-bone (7.7%), and 12 tendon/ligaments (15.4%) with 8 (10.2%) of the studies specifically in menisci. Methods used to reduce immune response include freezing, irrigation, and immunosuppressant administration. Recorded histological evidence of immune response included cell apoptosis, type II collagen increase, interleukins (IL) secretion, and increased lymphocytes/plasma cells in the synovial fluid. The pathways proposed were mismatched in cell-surface proteins as many studies conducted major histocompatibility complex (MHC) class I matching, which reduced the immune response. Despite histological evidence, including HLA sensitization after transplant signaling an immune response, clinical significance was not observed. Recent clinical experience of increased magnetic resonance imaging (MRI) signal response to orthopedic allografts, along with patient symptoms, has raised questions about rejection. Clinical rejection reports are limited in this review. This immune response to orthopedic allografts must be considered, and additional studies are needed to explore the relationship between rejection and clinical outcomes. This scoping review indicates that there is a range of human and animal studies demonstrating various immunologic response presentations and severities with different orthopedic tissue allografts.