Cellular immunity to rabbit types I, 11, and I11 collagen was detected after both partial medial meniscectomy and sham operations in rabbits when an in vitro 'H-thymidine incorporation assay was used. The blastogenic responses were commonly directed toward peptides derived from collagens by cyanogen bromide cleavage used to mimic proteinase degradation products. The responses to type 111 collagen peptides were by far the strongest and were seen in most rabbits that were operated on. We suggest that the responses to types I and I1 collagen were caused by a cross-reaction with type I11 collagen peptides. This conclusiorl was supported by the observation that spleen cells from rabbits directly immunized with homologous type 111 collagen peptides in Freund's complete adjuvant responded strongly to the immunizing peptides and also crossreacted with types I and I1 collagen peptides. Immunity to cartilage proteoglycans was observed primarily in rabbits that had undergone meniscectomy and had severe cartilage degeneration. These results indicated that immunity to collagens will develop merely as a result of joint surgery, whereas immunity to proteoglycans is largely dependent upon an osteoarthritic lesion.Osteoarthritis is a disease of diarthrodial joints characterized by fibrillation and fissuring of articular cartilage not directly attributable to an inflammatory process (1). The etiology of this disease is unknown but the primary event appears to involve damage to the cartilage matrix, perhaps as a result of abnormal biomechanical stresses. Proteoglycans are depleted from articular cartilage (2) even though there is a concomitant increase in proteoglycan synthesis by chondrocytes (3). These cells also proliferate, forming clones, in an attempt to repair the damaged matrix.Although the disease is classically considered to be noninflammatory, there is at least low-level inflammatory involvement in many cases (1). The histology of the synovium can even appear very similar to that seen in inflammatory arthritides, with lymphocytic and plasma cell involvement. However, there has been, to date, very little evidence to suggest a role for the immune system in the pathogenesis of osteoarthritis, although immunoglobulins and complement can be demonstrated in many cartilage samples from patients (4).We have recently demonstrated the development of autoimmunity to cartilage proteoglycans and collagens after gross destruction of articular tissues in a rabbit model of chronic inflammatory arthritis (5). In the present study we explored whether such immunity to connective tissue macromo~ecu~es could also develop in rabbits with experimental osteoarthritis. In such disease, the destruction of articular cartilage is thought to occur without the direct involvement of an inflammatory process- MATERIALS AND METHODSPreparation of cartilage proteogiycans. Costal cartilage was collected from normal rabbits (4-6 months old) and