Treatment with an anti-CD4 monoclonal antibody strongly ameliorates established rat adjuvant arthritis

Abstract

SUMMARYSome experimental arthritic diseases can be prevented by treatment with anti-CD4 MoAbs. Trials with ongoing disease have not been successful so far. The aim of this study was to ascertain whether W3/25 could reverse adjuvant arthritis (AA), when beginning treatment on day 14, i.e. when the disease was established. Moreover, one group of animals treated with the anti-CD4 MoAb received OX8 MoAb at the same time, thus depleting CD8 cells from circulation. During treatment with W3/25, a strong amelioration of inflammatory signals was observed, as assessed by means of paw volume increase and arthritic score. However, when treatment stopped, a rebound to arthritis signals occurred. The parallel depletion of CD8 cells did not modify these effects, thus the combined treatment W3/25 OX8 gave the same amelioration as treatment with W3/25 alone. These findings indicate that CD4 cells play an important role in perpetuating rat AA. Moreover, CD8 cells do not seem to have a regulatory role in the CD4 cells responsible for the inflammatory response.

Treatment with depleting CD4 monoclonal antibody results in a preferential loss of circulating naive T cells but does not affect IFN-gamma secreting TH1 cells in humans.

“…Indeed, a number of experimental animal models have shown that (auto)antigen reactive CD4 pos TH1-type cells are of crucial importance for disease induction and disease progression (10)(11)(12). In accordance with this notion, in vivo depletion of CD4 pos T cells interferes with disease induction in experimental allergic encephalomyelitis (13)(14)(15)(16), adjuvant arthritis (17), collagen-induced arthritis (18), experimental autoimmune glomerulonephritis (19), experimental antiphospholipid syndrome, and systemic lupus erythematosus (20).…”

Effector T cells in rheumatoid arthritis: Lessons from animal models

“…+ mAb treatment of established AIA had no effect on disease, and transfer of CD8 + T cells from arthritic rats into DA recipients failed to establish disease [18,49]. Conversely, the spontaneous development of disease in K/BÂN mice improved within 5 days of CD8 depletion [165].…”

“…In AA Administration of anti-CD4 Ab to rats with established AA ameliorated disease, but disease rebounded after withdrawal [18]. Antigen-induced arthritis (AIA) is a model of inflammatory arthritis which is induced by the intraarticular injection of methylated bovine serum albumin (mBSA).…”

“…On the other hand, the knockout or mutation of key T cell subsets, the cytokines and/or signalling molecules they are associated with [12,13], and the use of depleting or non-depleting antibodies (Ab) [14][15][16][17][18][19][20][21], have allowed for a more specific understanding of the direct contribution of certain factor(s) to disease initiation, maintenance, or amelioration. Pro-and anti-inflammatory cytokines and chemokines and/or their receptors, key mediators of the effector function of T cells, appear to be centrally involved in the pathogenesis of RA [22].…”

CD4 Expression Decrease by Antisense Oligonucleotides: Inhibition of Rat T CD4+Cell Reactivity

“…In this regard, anti-CD4 monoclonal antibodies (mAb) efficiently induce immune tolerance in the treatment of human and experimental autoimmune diseases (Mauri et al, 1997;Isaacs et al, 1999;reviewed in Nepom, 2002) and in the prevention of transplantation rejection (Mottram et al, 1998;Motoyama et al, 2000; reviewed in Adler and Turka, 2002). Anti-CD4 mAb therapy prevents and improves rat adjuvant arthritis (Pelegrí et al, 1995(Pelegrí et al, , 1996 associated with a decrease in Th1-like cells (Pelegrí et al, 2001). In addition, it has proved efficient in other animal models of rheumatoid arthritis (Van den Broek et al, 1992;Chu and Londei, 1996;Mauri et al, 1997) and in clinical studies (Van der Lubbe et al, 1997;Schulze-Koops et al, 1998).…”