Novel Th17 Lymphocyte Populations, Th17.1 and PD1+Th17, are Increased in Takayasu Arteritis, and Both Th17 and Th17.1 Sub-Populations Associate with Active Disease

Purpose: We evaluated T helper lymphocyte profile, including novel Th17 subsets Th17.1 (secrete IFN-gamma, associate with corticosteroid resistance) and PD1+Th17 (secrete TGF-beta 1, implicated in fibrosis), and related cytokines in peripheral blood of Takayasu arteritis (TAK). Materials and Methods: We evaluated circulating Th1, Th2, Th17, Th17.1, PD1+CD4+ T lymphocytes, PD1+Th17, and Treg lymphocytes, inflammatory (IFN-gamma, IL-4, IL-6, IL-17A, IL-23, IL-1 beta, TNF-alpha) and regulatory (IL-10, TGF-beta 1) cytokines in peripheral blood of TAK (n = 57; median age 35 (interquartile range 26-45) years; 40 females) in a cross-sectional design. We studied inflammatory and regulatory cytokines in culture supernatant of peripheral blood mononuclear cells (PBMCs) from TAK following stimulation with antiCD3/anti-CD28 and their modulation by tacrolimus (immunosuppressive) with/without tadalafil (anti-fibrotic). Furthermore, we followed up immunosuppressive-naive active TAK (n = 16) and compared T helper lymphocyte populations and cytokines before and after immunosuppressive therapy. Healthy controls (HC, n = 21) and sarcoidosis (disease control, n = 11) were compared against TAK. Results: TAK had higher Th17, Th17.1 and PD1+Th17 lymphocytes than HC (p < 0.001), and higher PD1+CD4+ T lymphocytes than sarcoidosis (p < 0.001). Th17 lymphocytes associated with active TAK after multivariable-adjusted logistic regression (p = 0.008). TAK had greater cytokine secretion from PBMCs (IFN-gamma, IL-17A, IL-10 versus HC; IL-6, TNF-alpha, IL-1 beta versus HC or sarcoidosis) (p < 0.05). In-vitro, PBMCs from TAK showed reduced secretion of all inflammatory cytokines with tacrolimus, with synergistic reduction in IL 17A, IL-6, IL-1 beta and IL-10 following addition of tadalafil to tacrolimus. Serial follow-up of immunosuppressive-naive TAK (n = 16) showed reduction in serum IL-6 and TGF-beta 1 (p < 0.05) and IL-6 in culture supernatant (p < 0.05) following immunosuppressive therapy. Conclusion: Novel Th17 sub-populations (Th17.1 and PD1+Th17) are elevated in TAK. Th17 lymphocytes associate with active TAK. In-vitro experiments on cultured PBMCs suggest promise for further evaluation of a combination of immunosuppressive tacrolimus with anti-fibrotic tadalafil (or other anti-fibrotic therapies) in clinical trials of TAK.