Background/Purpose: Nearly 2% of the US population suffers from inflammatory arthritis, and while there are effective treatments that reduce the joint destruction, over 20% of affected individuals to do derive benefit from currently available treatments. We have previously described the bone sparing effect of a stem cell recruiting peptide (LLP2A) chemically linked to the osteoaffinity compound alendronate.  The goal of this experiment was to determine if the hybrid compound, LLP2A-Ale, alone or in combination with concomitantly administered mesenchymal stem cells (MSCs) could reduce inflammatory joint destruction in the collagen induced arthritis model and if there was an immunomodulating role of MSCs in the inflammatory joint and in the lymphoid tissues. 

Methods: 8-week-old DBA1/J male mice were immunized with CFA/100 μg chicken collagen (Chondrex Inc) and on Day 21 boosted with 100 μg chicken collagen in IFA subcutaneously.  On Day 22 the mice were randomized into groups and received the individual treatments: PBS, vehicle (2% DMSO), alendronate 500ug/kg ip, LLP2A-Ale 250 ug/kg iv, LLP2A-Ale 500 ug/kg, MSC 2×10⁶, MSC+LLP2A-Ale 250 ug/kg iv, or MSC+ LLP2A-Ale 500ug/kg iv. On Day 24 all mice received 50ug LPS in NS and were sacrificed on day 48.  Study endpoints included ankle thickness assessed with microcalipers, 28 joint count for swelling, histologic assessment of right hind limbs (erosion, cartilage thickness, inflammation), bone volume assessed by microCT of left hind limb, levels of anti-CII antibodies and serum cytokines by Luminex.  Lymph nodes and spleen were analyzed by flowcytometry. Each experiment was performed on two occasions.

Results: Mice developed clinically detectable arthritis on day 23 (two days after the boost with IFA/CII) and the swelling resolved by day 35.  Arthritis developed in all immunized groups; however all of the treatment groups had statistically significantly less swelling and lower joint scores than the mice treated with vehicle (AUC for swelling p<0.001 for all treated groups from vehicle).  There was a trend toward lower levels of anti-CII antibodies in the treatment groups compared to the vehicle control.  There were no significant differences in the number of CD4+CD25+FoxP3+ T regs in the draining lymph nodes or in the splenic B220+, CD4+ or CD8+ populations.  There was an incresae in splenic Gr1+ cells. The vehicle treated group had significant histological changes compared to nonarthritis controls, but was not statistically difference than other treated mice. Erosive changes were confirmed in microCT scans of the knee joints; however there were no significant differences in the bone volume density of the distal femur, proximal tibia and the paws. There was an overall trend toward increased cytokine production in mice treated with MSCs.

Conclusion: reatment of CIA with LLP2A-Ale with and without MSCs appeared to reduce joint swelling, with modest effects on immune modulation and joint tissue destruction.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/treatment-of-inflammatory-arthritis-with-a-hybrid-compound-llp2a-ale-can-prevent-joint-destruction/