Programmed Cell Death-1 Pathway Deficiency Enhances Autoimmunity Leading to Dacryoadenitis of Mice

Programmed cell death protein (PD)-1 is a coinhibitory molecule that suppresses immune response and maintains homeostasis. Moreover, the PD-1 pathway blocks cancers from being attacked by cells. Anti–PD-1 antibody therapy such as nivolumab improves survival in cancer patients. However, occurrence of autoimmune inflammatory disorders various organs has been increasingly reported an adverse effect nivolumab. Of associated with nivolumab, Sicca syndrome occurs 3% to 11% cases unknown pathologic mechanisms. Whether absence causes functional morphologic lacrimal glands was determined analyzing gene–knockout (Pdcd1−/−) mice. Histopathologic analysis showed Pdcd1−/− mice developed dacryoadenitis beginning at 3 4 months age, deteriorated age. Flow-cytometric confirmed cells infiltrating affected consisted mainly CD3+ T only small proportion CD19+ B Among cells, CD4+ Th-cell subset Th1 producing interferon-γ early stage Experiments lymphocyte transfer into irradiated wild-type induced dacryoadenitis. These results indicate plays important role prevention caused activated Coinhibitory molecules, cytotoxic lymphocyte–associated antigen (CTLA)-4, B- T-lymphocyte attenuator (BTLA), programmed protein, negatively drive cell–mediated maintain homeostasis.1Sharpe A.H. Freeman G.J. The B7-CD28 superfamily.Nat Rev Immunol. 2002; 2: 116-126Crossref PubMed Scopus (1355) Google Scholar,2Chen L. Co-inhibitory molecules family control T-cell immunity.Nat 2004; 4: 336-347Crossref (1016) Scholar Ctla-4–deficient develop massive lymphoproliferative disease leading destruction multiple organs, die weeks age.3Tivol E.A. Borriello F. Schweitzer A.N. Lynch W.P. Bluestone J.A. 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Serum 1:100 dilution. concentration ELISA (R&D Systems Minneapolis, MN) ELISA, 6-month-old homogenized radioimmunoprecipitation homogenizer. statistical comparisons groups, parametric (histologic scores SMGs experiments) had variances tested Welch t-test, nonparametric (tear volumes, levels) U-test. SMGs, two-way variance Tukey post hoc test used. P < 0.05 considered statistically significant. secretion Figure significantly less compared (Figure 1A). While there no differences months, much le