Suppression of Rheumatoid Arthritis by Enhanced Lymph Node Trafficking of Engineered Interleukin‐10 in Murine Models

Abstract

Objective. Rheumatoid arthritis (RA) is a major autoimmune disease that causes synovitis and joint damage. Although clinical trials have been performed using interleukin-10 (IL-10), an antiinflammatory cytokine, as a potential treatment of RA, the therapeutic effects of IL-10 have been limited, potentially due to insufficient residence in lymphoid organs, where antigen recognition primarily occurs. This study was undertaken to engineer an IL-10-serum albumin (SA) fusion protein and evaluate its effects in 2 murine models of RA.Methods. SA-fused IL-10 (SA-IL-10) was recombinantly expressed. Mice with collagen antibody-induced arthritis (n = 4-7 per group) or collagen-induced arthritis (n = 9-15 per group) were injected intravenously with wild-type IL-10 or SA-IL-10, and the retention of SA-IL-10 in the lymph nodes (LNs), immune cell composition in the paws, and therapeutic effect of SA-IL-10 on mice with arthritis were assessed.Results. SA fusion to IL-10 led to enhanced accumulation in the mouse LNs compared with unmodified IL-10. Intravenous SA-IL-10 treatment restored immune cell composition in the paws to a normal status, elevated the frequency of suppressive alternatively activated macrophages, reduced IL-17A levels in the paw-draining LN, and protected joint morphology. Intravenous SA-IL-10 treatment showed similar efficacy as treatment with an anti-tumor necrosis factor antibody. SA-IL-10 was equally effective when administered intravenously, locally, or subcutaneously, which is a benefit for clinical translation of this molecule.Conclusion. SA fusion to IL-10 is a simple but effective engineering strategy for RA therapy and has potential for clinical translation.

Macrophage-Targeted Hydroxychloroquine Nanotherapeutics for Rheumatoid Arthritis Therapy

“…MP-HCQ treatment also exhibited a high anti-inflammatory effect in BMDMs, similar to RAW274.7 cells, with significantly declined IL-6 (** p , *** p ) and inclined IL-10 secretion (Figure b). Studies have shown that the administration of exogenous IL-10 could inhibit the production of inflammatory cytokines in synovial tissues and prevent the production of pro-inflammatory cytokines, such as IL-5, IL-6, and IL-27 . The high IL-10/IL-6 ratio of MP-HCQ-treated BMDMs (Figure b) underlined a highly favorable microenvironment to alleviate the inflammation.…”

“…Studies have shown that the administration of exogenous IL-10 could inhibit the production of inflammatory cytokines in synovial tissues and prevent the production of proinflammatory cytokines, such as IL-5, IL-6, and IL-27. 48 The high IL-10/IL-6 ratio of MP-HCQ-treated BMDMs (Figure 2b) underlined a highly favorable microenvironment to alleviate the inflammation. It is noticed that empty polymersome MP did not affect the secretion of these cytokines, and free HCQ had only limited secretion of IL-10.…”

Immunomodulatory Microparticles Epigenetically Modulate T Cells and Systemically Ameliorate Autoimmune Arthritis

“…While the IA agent suppressed arthritis in treated joints, it did not display systemic efficacy. [ 72 ] PLGA‐ATRA MP have the advantage of acting locally at the site of inflammation to promote disease‐specific immunomodulation without a priori knowledge of participating epitopes. Other methods using biomaterial depots to expand T reg have used PLGA microparticles encapsulating multiple immunoregulatory agents, such as rapamycin, IL‐2, and TGF‐ β that, when injected near hind paw draining lymph nodes, modulated disease but also resulted in a systemic immunosuppression and nonspecific expansion of T reg .…”

Influence of IL10 and TGFB1 Promoter Polymorphisms on Serum Cytokine Levels in Development and Severity of RA

“…However, the complex nature of RA immunopathogenesis is influenced by several intrinsic and extrinsic factors, and the pleiotropic nature of IL-10 makes this aim difficult. The previous clinical trials showed a limited therapeutic effect of IL-10, but the studies continue these days in an attempt to offer a new IL-10-based strategy for RA therapy [ 19 ].…”

“…Genotyping for the -1082A/G polymorphism in the IL10 gene (rs1800896) was performed by an amplification refractory mutation system (ARMS)–PCR assay using a forward primer specific for G allele 5′-CCTATCCCTACTTCCCCC-3′, a forward primer specific for A allele 5′-CCTATCCCTACTTCCCCT-3′ and a reverse generic primer 5′AGCAACCACTCCTCGTCGCAAC-3′. The parameters of thes PCR protocol were the same as described by Miteva et al [ 19 ].…”