NAD+ protects against EAE by regulating CD4+ T-cell differentiation

CD4+ T cells are involved in the development of autoimmunity, including multiple sclerosis (MS). Here we show that nicotinamide adenine dinucleotide (NAD+) blocks experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by inducing immune homeostasis through CD4+IFNγ+IL-10+ T cells and reverses disease progression by restoring tissue integrity via remyelination and neuroregeneration. We show that NAD+ regulates CD4+ T-cell differentiation through tryptophan hydroxylase-1 (Tph1), independently of well-established transcription factors. In the presence of NAD+, the frequency of T-bet−/− CD4+IFNγ+ T cells was twofold higher than wild-type CD4+ T cells cultured in conventional T helper 1 polarizing conditions. Our findings unravel a new pathway orchestrating CD4+ T-cell differentiation and demonstrate that NAD+ may serve as a powerful therapeutic agent for the treatment of autoimmune and other diseases

Supplementary Material for: High Expression of Major Histocompatibility Complex Class I in Clear Cell Renal Cell Carcinoma Is Associated with Improved Prognosis

<b><i>Introduction:</i></b> In this study we analyzed major histocompatibility complex class I (MHCI) expression as a potential prognostic immune marker for patients with clear cell renal cell carcinoma (ccRCC). <b><i>Patients and Methods:</i></b> 34 patients with localized ccRCC (pT1-pT3) who had undergone nephrectomy and had at least 4 years of clinical follow-up data were included in the study. Immunohistochemical staining for MHCI was performed on tumor sections. An automated image analysis algorithm was applied to representative tumor areas to quantitate the proportion of stained pixels (positivity score = positive pixels/total pixels) on scanned digital slides. <b><i>Results:</i></b> At the end of the study, the patients who were alive had increased MHCI expression (mean positivity score 0.80) compared to those who died of the disease (mean positivity score 0.53; p < 0.0001, t test). Patients who were alive with recurrence had increased MHCI expression (positivity score 0.81) compared to those who succumbed to their disease recurrence (positivity score 0.53; p < 0.0001, t test). Survival was higher among patients with high MHCI expression compared to patients with low MHCI expression (p < 0.0001, Mantel-Cox). <b><i>Conclusions:</i></b> With an automated high-throughput image analysis technique, this study shows that higher tumor cell MHCI expression promotes increased survival and reduced incidence of recurrence compared to patients with lower tumor cell MHCI expression

Major histocompatibility complex I upregulation in clear cell renal cell carcinoma is associated with increased survival

Objective: To examine the prognostic value of tumor major histocompatibility complex I (MHCI) expression on survival and recurrence in patients with clear cell renal cell carcinoma (RCC). Methods: Fifty-three patients that underwent nephrectomy at our institution for clear cell RCC (T1–T3) with ≥4 years of follow-up were queried from our nephrectomy database. Immunohistochemical staining for MHCI was performed on tumor specimens and MHCI expression was quantified with an automated image analysis technique. Patients were divided into high and low MHCI expression groups in order to study the relationship between MHCI expression and prognosis using the Kaplan–Meier method and log-rank test. Results: Overall survival and recurrence free survival were increased in the high MHCI expression group compared to the low MHCI expression group (log-rank, p = 0.036 and p = 0.028, respectively). Patients alive at the end of the study had higher MHCI expression (mean positivity score 0.82) than those that died of disease (mean positivity score 0.76, t test, p = 0.030). Patients that did not develop recurrence during the study period had higher MHCI expression (mean positivity score 0.83) than those that did develop recurrence (mean positivity score 0.78), but this difference was not significant (t test, p = 0.079). Conclusion: Our data demonstrate that high MHCI expression confers improved overall and recurrence free survival in patients with clear cell RCC and could serve as an important prognostic tool in identifying high-risk patients. Keywords: Renal cell carcinoma, Prognosis, MHCI, Biomarke