Inhibition of the development of collagen-induced arthritis in rhesus monkeys by a small molecular weight antagonist of CCR5.
OBJECTIVE
Collagen-induced arthritis (CIA) in the rhesus monkey is a nonhuman primate model of rheumatoid arthritis (RA). The close phylogenetic relationship between humans and the rhesus monkey makes this model useful for the preclinical safety and efficacy testing of new therapies that are inactive in animals more distinctly related to humans. In this study, we tested the therapeutic potential of a novel, small molecular weight antagonist of CCR5, SCH-X, in this model.


METHODS
CIA was induced in 10 rhesus monkeys. The animals were allocated to receive SCH-X or saline as the control (n = 5 in each group). Treatment was initiated on the day of CIA induction and continued for 45 days. Monkeys were monitored before and 63 days after CIA induction for macroscopic signs of clinical arthritis, such as soft-tissue swelling and body weight. Furthermore, markers of inflammation and joint degradation were monitored to follow the disease course.


RESULTS
Only 2 of 5 animals in the SCH-X-treated group displayed prominent soft-tissue swelling, compared with all 5 saline-treated monkeys. In addition to the suppression of joint inflammation, treatment with SCH-X resulted in a reduction in joint destruction, as demonstrated by lower rates of urinary excretion of collagen crosslinks, with confirmation by histology. Whereas in all saline-treated monkeys, marked erosion of joint cartilage was observed, this was absent in 4 of the 5 SCH-X-treated monkeys.


CONCLUSIONS
The systemic effects of treatment with SCH-X were a suppressed acute-phase reaction (reduction in C-reactive protein level) in the 3 treated monkeys with CIA that remained asymptomatic, and an altered antibody response toward type II collagen. The results suggest that the CCR5 antagonist SCH-X might have a strong clinical potential for treatment during periods of active inflammation, as seen in RA.
Vierboom
Michel P M
MP
Biomedical Primate Research Centre, Rijswijk, The Netherlands.
Zavodny
Paul J
PJ
Chou
Chuan-Chu
CC
Tagat
Jayaram R
JR
Pugliese-Sivo
Catherine
C
Strizki
Julie
J
Steensma
Ruo W
RW
McCombie
Stuart W
SW
Celebi-Paul
Liesbeth
L
Remarque
Ed
E
Jonker
Margreet
M
Narula
Satwant K
SK
Hart
Bert't
B
D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D065100:CCR5 Receptor Antagonists; D002358:Cartilage, Articular / Q000473:pathology; D024043:Collagen Type II; D005500:Follow-Up Studies; D008253:Macaca mulatta; D008297:Male
D065100:CCR5 Receptor Antagonists; D024043:Collagen Type II