Treatment with anti-C5aR mAb leads to early-onset clinical and mechanistic effects in the murine delayed-type hypersensitivity arthritis model

Abstract

(2015) Treatment with anti-C5aR mAb leads to earlyonset clinical and mechanistic effects in the murine delayed-type hypersensitivity arthritis model, Autoimmunity, 48:7, 460-470, DOI: 10.3109/08916934.2015 Department of Cell Biology, Novo Nordisk A/S, Beijing, China AbstractBlockade of the complement cascade at the C5a/C5a receptor (C5aR)-axis is believed to be an attractive treatment avenue in rheumatoid arthritis (RA). However, the effects of such interventions during the early phases of arthritis remain to be clarified. In this study we use the murine delayed-type hypersensitivity arthritis (DTHA) model to study the very early effects of a blocking, non-depleting anti-C5aR mAb on joint inflammation with treatment synchronised with disease onset, an approach not previously described. The DTHA model is a single-paw inflammatory arthritis model characterised by synchronised and rapid disease onset driven by Tcells, immune complexes and neutrophils. We show that a reduction in paw swelling, bone erosion, cartilage destruction, synovitis and new bone formation is apparent as little as 60 h after administration of a single dose of a blocking, non-depleting anti-mouse C5aR mAb. Importantly, infiltration of neutrophils into the joint and synovium is also reduced following a single dose, demonstrating that C5aR signalling during the early stage of arthritis regulates neutrophil infiltration and activation. Furthermore, the number of T-cells in circulation and in the draining popliteal lymph node is also reduced following a single dose of anti-C5aR, suggesting that modulation of the C5a/C5aR axis results in effects on the T cell compartment in inflammatory arthritis. In summary, these data demonstrate that blockade of C5aR leads to rapid and significant effects on arthritic disease development in a DTHA model strengthening the rationale of C5aR-blockade as a treatment strategy for RA, especially during the early stages of arthritis flare.

C5a receptor (CD88) promotes motility and invasiveness of gastric cancer by activating RhoA

“…Recent studies indicate that C5aR (CD88) has a function in many different tissues, including the lung, heart, liver and kidneys [23–27], and that C5a is associated with many clinical conditions, including sepsis and rheumatoid arthritis [28–30]. We previously reported that C5a promoted the mobility and invasive ability of cancer cells, such as cholangiocarcinoma cells [15, 25].…”

Pharmacological Value of Murine Delayed‐type Hypersensitivity Arthritis: A Robust Mouse Model of Rheumatoid Arthritis in C57BL/6 Mice

“…However, it has been shown that immune complexes can increase vasopermeability at the sites of distal joints, which leads to accumulation of anti‐CII in the joints , so a contributing role of anti‐mBSA antibodies cannot be ruled out. Blocking C5aR signalling in DTHA reduces arthritis severity , supporting the role of complement and myeloid cell activation in the model's pathogenesis. Based on the available studies , the current hypothesis for disease development is that activated mBSA‐specific CD4 + T cells provide the initial inflammatory stimulus in the extra‐articular tissue of the paw, which leads to production of inflammatory mediators that recruit and activate neutrophils, macrophages and osteoclasts.…”

“…Blocking C5aR signalling in DTHA reduces arthritis severity , supporting the role of complement and myeloid cell activation in the model's pathogenesis. Based on the available studies , the current hypothesis for disease development is that activated mBSA‐specific CD4 + T cells provide the initial inflammatory stimulus in the extra‐articular tissue of the paw, which leads to production of inflammatory mediators that recruit and activate neutrophils, macrophages and osteoclasts. Depletion of CD4 + T cells completely inhibits disease development, which shows their indispensable role.…”

“…Twelve hours after challenge, the neutrophil chemoattractants CXCL10 and CXCL2 are markedly up‐regulated in the inflamed paw, and on day 2 after arthritis induction, 60% of the infiltrating CD45 + cells are neutrophils . Complement activation also takes place, as increased levels of C5a can be measured in the affected paws . C5a does not contribute to the recruitment of macrophages in the model, but other monocyte and macrophage chemoattractants and survival factors are up‐regulated in the inflamed paws, including CCL2 and granulocyte macrophage colony‐stimulating factor (GM‐CSF) .…”

Complement—here, there and everywhere, but what about the transplanted organ?

“…Anti-CD88 monoclonal antibody has been reported to dramatically decrease joint inflammation in a murine model of arthritis following a single treatment. It is thought to induce its effects by reducing neutrophil infiltration and activation whilst modulating circulating T cells [137]. A combination of these agents may provide effective therapy in the near future however the challenge of when and how long to use them for leads to the question of whether any biomarkers exist that may aid this decision making.…”