For patients with autoimmune disease, the research to date shows that the TNF-family cytokine TL1A and its receptor DR3 may be pathogenic.
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SAN FRANCISCO—To date, evidence on the efficacy of blocking the cytokine tumor necrosis factor (TNF) and its receptors in autoimmune diseases has resulted in the approval by the Food and Drug Administration (FDA) of five anti-TNF agents. Less well known, according to Richard Siegel, MD, PhD, chief, Immunoregulation Section, Autoimmunity Branch, and Clinical Director, NIAMS, National Institutes of Health, Bethesda, Md., are 17 other cytokines genetically and structurally related to TNF that comprise the TNF superfamily and play a significant role in autoimmune diseases. Each of these cytokines, along with each cytokine receptor, play a different role in disease activation, and ongoing research is looking at how these cytokines work alone or in combination in the pathogenesis of autoimmune diseases to further uncover potential therapeutic targets.
In the session, Tumor Necrosis Factor (TNF) and Beyond: The TNF-Tumor Necrosis Factor Receptor Cytokine Superfamily From Bench to Bedside, at the 2015 ACR/ARHP Annual Meeting, a panel of experts talked about the biology and therapeutic relevance of the tumor necrosis factor receptor (TNFR) family ligands and receptors to rheumatology. Among the talks were presentations on specific cytokines, TL1A and OX40L, and evidence on their role in pathogenesis of autoimmune diseases and early data on potential targets for therapy.
Cytokine TL1A & Receptor DR3
Dr. Siegel opened the session by describing the current research on TL1A and its receptor, DR3.
Dr. Siegel
Past research has shown that TNF cytokines share very specific functions and that many mutations linked to these shared functions are linked to diseases. Importantly, he said that 32 of 98 genes encoding these shared functions of TNF cytokines (TNFSF) and their receptors (TNFSRSF) are associated with at least one autoimmune disease.
Thus, blockade of TNF cytokine signaling may provide a successful therapeutic strategy.
Toward that ultimate goal, he talked about current and ongoing research on the specific cytokine, TL1A, also known as TNFSF15.1 For patients with autoimmune disease and, particularly those with rheumatic disease, he said the research to date shows that the TNF-family cytokine TL1A and its receptor DR3 may be pathogenic.
From mouse models, the research shows that TL1A is a co-stimulator of lymphocyte activation and is essential for the development of mouse models of various autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and asthma, he said.
For example, he highlighted data showing that blocking TL1A in mice models of colitis showed a remarkable benefit in preventing pathology and demonstrated a significant effect on acute TL1A. Similar data were obtained from a mice model that showed the efficacy on preventing erosions in blocking TL1A in mice with collagen-induced arthritis.
From human studies, evidence shows that TL1A is elevated in the serum specifically in patients with rheumatoid arthritis and declines in response to TNF blocking therapy. “This suggests that [TL1A] may be a biomarker for TNF in RA,” said Dr. Siegel.
Overall, Dr. Siegel emphasized that TL1A, along with other members of the TNF cytokine family, may become therapeutic targets for rheumatic disease “in addition to TNF, RANK-ligand and BlyS, which are currently targeted by FDA-approved therapeutics.”
Cytokine OX40L & Receptor OX40
Michael Croft, PhD, professor and head, Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, Calif., spoke on the importance of another cytokine of the TNF superfamily—OX40L and its receptor OX40. He said that OX40 signals enhance and sustain division and survival of T cells, and drive T cell clonal expansion and T cell memory (both CD4+ and CD8+ T cells). Thus, targeting OX40 to reduce pathologic T cell activity is also of interest in ongoing studies.
From human studies, evidence shows that TL1A is elevated in the serum specifically in patients with rheumatoid arthritis & declines in response to TNF blocking therapy. ‘This suggests that [TL1A] may be a biomarker for TNF in RA.’ —Dr. Siegel.
Evidence from mouse models has shown that blocking OX40 reduces the pathology, often to a great extent, of many diseases, such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, asthma and diabetes.
Dr. Croft
Based on the efficacy in these studies, several phase I clinical trials are underway. To date, he said, one study has gone into phase II trial that looked at the effect of anti-OX40L in mild allergic asthma.2 The study included 28 patients with mild, atopic asthma randomized to an anti-OX40L monoclonal antibody (MAb) or placebo. To assess late-phase asthmatic response, the primary endpoint of the study, patients were administered allergen inhalation challenges at 56 and 113 days following the first dose of the study drug. Early-phase asthmatic response was also assessed.
The study found no difference between the two groups in early- or late-phase asthmatic response. The failure of OX40L blockade to meet the trial endpoints was surprising, said Dr. Croft, given the large evidence on this benefit in mouse models.
Further analysis of the data from the mice studies, however, showed that the efficacy of blocking OX40L may be limited to a specific small window of time. Together with other data showing enhanced expression of OX40L primarily in patients undergoing asthma exacerbations and a correlation with severe asthma, according to Dr. Croft, this suggests that trials of the efficacy of anti-OX40L therapy should target patients with severe asthma as the main endpoint.
However, he emphasized that blocking one molecule may not work well in many complex diseases and that the temporal understanding of when to deliver treatment for optimal outcome as suggested in the mice studies is too simplistic for human disease.
As such, he pointed to data that show a possible crossover effect of several molecules in the TNF family when working together. For example, a model of asthma showed no therapeutic benefit when only blocking OX40L but significant activity when blocking both OX40L and CD30L. Dr. Croft suggested that this paradigm is likely to translate to other inflammatory and autoimmune diseases where combination therapy may be needed to gain significant therapeutic benefits.
Mary Beth Nierengarten is a freelance medical journalist based in St. Paul, Minn.
References
- Richard AC, Ferdinand JR, Meylan F, et al. The TNF-family cytokine TL1A: From lymphocyte costimulator to disease co-conspirator. J Leukoc Biol. 2015;98:333–345.
- Gauvreau GM, Boulet LP, Cockcroft DW, et al. OX40L blockade and allergen-induced airway responses in subjects with mild asthma. Clin Exp Allergy. 2014;44(1):29–37.
