Anti-CD8 treatment reduces the severity of inflammatory arthritis, but not vasculitis, in mercuric chloride-induced autoimmunity

Abstract

SUMMARYMercuric chloride (HgCl 2 ) induces a T cell-dependent autoimmune syndrome in Brown-Norway (BN) rats characterized by a humoral response, tissue injury with an accumulation of CD8 and CD4 T cells, and an increase in tissue IL-4 mRNA and serum IgE suggesting Th2 cell activation. In other models of autoimmune disease, CD8 cells act in both anti-and pro-inflammatory capacities, suggesting that functionally distinct CD8 populations exist in vivo. The effect of treatment with OX8, a depleting anti-CD8 MoAb, on the initiation of HgCl 2 -induced autoimmunity was assessed in two experiments in a total of 20 BN rats, and compared with 20 animals treated with a control MoAb or PBS. OX8 significantly depleted peripheral blood CD8 lymphocytes, had no effect on HgCl 2 -induced anti-collagen or myeloperoxidase antibodies, nor on the incidence or severity of caecal vasculitis. The severity of HgCl 2 -induced arthritis was significantly reduced in OX8-treated animals; median peak score reduced from 7 . 5 to 3 . 0 (experiment 1) and from 7 . 0 to 4 (experiment 2) (P 0 . 009, Mann-Whitney U-test). OX8 treatment also exacerbated the early rise in HgCl 2 -induced IgE and induced a significant rise in plasma interferon-gamma (IFN-°), suggesting that CD8 cells may have a regulatory influence on Th cell populations. These data provide direct evidence that CD8 cells may act in a proinflammatory capacity in both this model of autoimmunity and the pathogenesis of inflammatory arthritis.

Epidemics of vascular toxicity and pulmonary hypertension: what can be learned?

“…Local endothelial damage was also apparent when mercury was injected intravenously by a drug addict [29]. Mercury is used as an experimental model for causing vasculitis in strains of genetically susceptible rats and guinea pigs, and similar changes have been observed in humans who suffer accidental exposure [30–32].…”

Monoclonal anti‐CD8 therapy induces disease amelioration in the K/BxN mouse model of spontaneous chronic polyarthritis

“…In different animal models of collagen‐induced arthritis (CIA), the absence of CD8+ T cells resulted in a reduced incidence (13, 14) and severity (15) of the disease. However, higher susceptibility was observed when animals were rechallenged (14, 15).…”

Resistance to re‐challenge in the Brown Norway rat model of vasculitis is not always complete and may reveal separate effector and regulatory populations

“…Although arthritis, vasculitis and serological changes are all known to be αβ T‐cell dependent, 7,11 with the large rise in IgE concentrations implicating the Th2 cell (following an interleukin‐4 driven IgE class switch), there are also clear differences in the pathogenesis of different aspects of the syndrome. Caecal vasculitis is unique in being partly neutrophil dependent 12 whilst the severity of arthritis alone demonstrates a CD8 dependence 13 . With both shared and unique aspects to pathogenesis, we would predict that if the mechanism of resistance were acting at a proximal level of pathogenesis, then resistance would be broad, affecting all aspects of the syndrome.…”

“…Caecal vasculitis is unique in being partly neutrophil dependent 12 whilst the severity of arthritis alone demonstrates a CD8 dependence. 13 With both shared and unique aspects to pathogenesis, we would predict that if the mechanism of resistance were acting at a proximal level of pathogenesis, then resistance would be broad, affecting all aspects of the syndrome. If, however, the mechanism of resistance was targeted on downstream unshared events, then differential regulation would be seen.…”