Discovery by National Eye Institute eases manufacturing and dosing of a promising drug candidate for the inflammatory eye disease uveitis and multiple sclerosis
October 17, 2017
NEI
Eyes with autoimmune uveitis show increased inflammatory cells in the eye (indicated by arrows). Treatment with p35 reduces this inflammatory response.  Credit: Charles Egwuagu.

NIH scientists have simplified manufacturing and dosing of a potential drug candidate for the autoimmune eye disease uveitis—a vision-threatening condition that accounts for about 15 percent of blindness in the U.S. The protein in question, part of the immune system signaling molecule interleukin-35 (IL-35), also shows efficacy in treating a mouse model of multiple sclerosis. The research was conducted at the National Eye Institute (NEI), part of the National Institutes of Health.   

In 2014, NEI researchers discovered that IL-35, which is secreted by antibody-producing B cells, dampens inflammation in the eyes of mice with autoimmune uveitis. IL-35 injections given on the same day of disease induction helped prevent uveitis, and when given up to 10 days after disease induction, IL-35 suppressed uveitis. The researchers found they could reverse uveitis in mice with injections of the regulatory B cells that produce IL-35.

Although the researchers successfully treated mice with lab-produced IL-35, IL-35 proved to be difficult to manufacture in sufficient quantities for therapeutic use because this cytokine is made of two interlocking proteins, p35 and Ebi3. In addition, the proteins easily bind and release each other in solution, creating uncertainty in determining the correct therapeutic dose. 

experimental autoimmune uveitis

Eyes with autoimmune uveitis show increased inflammatory cells in the eye (indicated by arrows). Treatment with p35 reduces this inflammatory response. Credit: Charles Egwuagu.

In a study published on September 28th in Nature Communications, the researchers show that the p35 subunit alone has anti-inflammatory properties and stimulates the production of B cells that dampen inflammation.

“We were able to recapitulate the activity of the heterodimer cytokine just by using one subunit, and that makes it a much more important contribution to the field of developing biologics to treat these diseases,” said the study’s lead investigator, Charles Egwuagu, MPH, Ph.D., chief of the Molecular Immunology section in NEI's Laboratory of Immunology.

In a forthcoming study in Frontiers in Immunology, the team showed that the p35 subunit is also effective in treating inflammation in a mouse model of multiple sclerosis, a disease in which the immune system attacks the protective covering of the nerves. In untreated mice, inflammatory immune cells penetrate the brain and spinal cord, causing paralysis in the mouse’s front and hind limbs and a flaccid tail. These traits were much reduced in mice treated with 100ng of p35, every other day until day 12 after initiation of the disease. That suggests p35 may hold promise as a treatment for certain neurodegenerative diseases. In these mouse models of MS, p35 induces the spleen to produce special populations of T and B cells that suppress inflammation in the brain and spinal cord.

The researchers are currently testing the effectiveness of p35 in treating other degenerative eye diseases such as diabetic retinopathy and macular degeneration. “These individual subunits may form a new generation of biologics that can be used to treat autoimmune and neurodegenerative diseases,” Egwuagu said.

References

Dambuza IM, He C, Choi JK, Yu CR, Wang R, Mattapallil MJ, Wingfield PT, Caspi RR, Egwuagu CE. 2017. IL-12p35 induces expansion of IL-10 and IL-35-expressing regulatory B cells and ameliorates autoimmune disease. Nat Commun. 2017 Sep 28;8(1):719. doi:10.1038/s41467-017-00838-4. Dambuza et al. Pubmed

Choi JK, Dambuza IM, He C, Yu CR, Uche AN, Mattapallil MJ, Caspi RR, Egwuagu CE. 2017. IL-12p35 inhibits neuroinflammation and ameliorates autoimmune encephalomyelitis.  Front. Immunol. 2017 Oct 5;8(1258). doi:10.3389/fimmu.2017.01258 Choi et al. Pubmed

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NEI leads the federal government’s research on the visual system and eye diseases. NEI supports basic and clinical science programs to develop sight-saving treatments and address special needs of people with vision loss. For more information, visit https://www.nei.nih.gov.

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