Combined Blockade of TNFα and IL-17A Ameliorates Progression of Collagen-Induced Arthritis without Causing Serious Infections in Mice

• Published in: The Journal of immunology (1950) 2019-02, Vol.202 (7), p.2017-2026
• Main Authors: Shen, Fang, Verma, Akash H., Volk, Amy, Jones, Brian, Coleman, Bianca M., Loza, Matthew J, Malaviya, Ravi, Moore, Beverley, Weinstock, Daniel, Elloso, M. Merle, Gaffen, Sarah L., Ort, Tatiana
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1801436

The cytokines TNFα and IL-17A are elevated in a variety of autoimmune diseases, including rheumatoid arthritis. Both cytokines are targets of several biologic drugs used in the clinic, but unfortunately many patients are refractory to these therapies. IL-17A and TNFα are known to mediate signaling synergistically to drive expression of inflammatory genes. Hence, combined blockade of TNFα and IL-17A represents an attractive treatment strategy in autoimmune settings where monotherapy is not fully effective. However, a major concern with this approach is the potential predisposition to opportunistic infections that might outweigh any clinical benefits. Accordingly, we examined the impact of individual versus combined neutralization of TNFα and IL-17A in a mouse model of rheumatoid arthritis (collagen-induced arthritis, CIA) and the concomitant susceptibility to infections that are likely to manifest as side effects of blocking these cytokines (oral candidiasis or tuberculosis). Our findings indicate that combined neutralization of TNFα and IL-17A was considerably more effective than monotherapy in improving CIA disease even when administered at a minimally efficacious dose. Encouragingly, however, dual cytokine blockade did not cooperatively impair antimicrobial host defenses, as mice given combined IL-17A and TNFα neutralization displayed infectious profiles and humoral responses comparable to mice given high doses of individual anti-TNFα or anti-IL-17A mAbs. These data support the idea that combined neutralization of TNFα and IL-17A for refractory autoimmunity is likely to be associated with acceptable and manageable risks of opportunistic infections associated with these cytokines.