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( 12 ) United States Patent US010119959B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 , 119 ,959 B2 Shen -Orr et al. ( 45 ) Date of Patent : Nov . 6 , 2018 ( 54 ) METHOD OF ASSAYING AN INDIVIDUAL Choi et al. , “ Combining multiple microarray studies and modeling FOR IMMUNE IMPAIRMENT interstudy variation ” , Bioinformatics , 2003 , vol. 19 , Suppl. 1 , pp . i84 - 190 . (75 ) Inventors : Shai S . Shen - Orr , Menlo Park , CA Cobb et al . , Application of genome- wide expression analysis to (US ) ; Atul J . Butte , Menlo Park , CA human health and disease, PNAS , Mar. 29 , 2005 , vol. 102, No . 13 , pp . 4801 -4806 . (US ) ; Mark M . Davis , Atherton , CA Coudeville et al. , “ Relationship between haemagglutination (US ) ; David Furman , San Francisco , inhibiting antibody titres and clinical protection against influenza : CA (US ) ; Brian A . Kidd , Palo Alto , development and application of a bayesian random - effects model” , CA (US ) Medical Research Methodology, 2010 , vol. 10 , 11 pgs . (73 ) Assignee : The Board of Trustees of the Leland Davis , “ A Prescription for Human Immunology ” , Immunity , Dec . 19 , 2008 , vol. 29 , No . 6 , pp . 835 - 838 . Stanford Junior University , Stanford , De Magalhaes et al . , “ The Human Ageing Genomic Resources : CA (US ) online databases and tools for biogerontologists ” , Aging Cell, Feb . 2009 , vol. 8 , No . 1 , pp . 65 -72 . ( * ) Notice : Subject to any disclaimer, the term of this De Visser et al . , “ Paradoxical roles of the immune system during patent is extended or adjusted under 35 cancer development” , Nature Reviews, Jan . 2006 , vol. 6 , pp . 24 -37 . U . S . C . 154 ( b ) by 199 days . Effros et al , “ The role of CD8+ T - cell replicative senescence in human aging ” , Immunological Reviews , 2005 , vol. 205 , pp . 147 (21 ) Appl. No. : 13 /168 ,974 157 . Evans et al ., “ The DAF - 2 Insulin -like Signaling Pathway Indepen ( 22 ) Filed : Jun. 25 , 2011 dently Regulates Aging and Immunity in C . Elegans" , Aging Cell , Dec . 2008 , vol. 7 , No . 6 , pp . 879 -893 . (65 ) Prior Publication Data Fagnoni et al. , “ Expansion of cytotoxic CD8 + CD28 - T cells in US 2012 / 0021414 A1 Jan . 26 , 2012 healthy ageing people , including centenarians” , Immunology 1996 , vol. 88 , pp . 501 -507 . Fagnoni et al ., “ Shortage of circulating naive CD8 + T cells provides Related U . S . Application Data new insights of immunodeficiency in aging” , Blood , May 1 , 2000 , vol. 95 , No. 9 , pp . 2860 - 2868. ( 60 ) Provisional application No . 61/ 358 , 884 , filed on Jun . Franceschi et al . , “ Inflamm - aging , An evolutionary Perspective on 25 , 2010 . Immunosenescence” , Annals New York Academy of Sciences , vol . 908 , pp . 244 - 254 . (51 ) Int. Ci. Frew , “ Allergen immunotherapy ” , J. Allergy Clin . Immunol, 2010 , GOIN 31 / 00 ( 2006 .01 ) vol. 125 , pp . S306 -S313 . GOIN 33 /50 ( 2006 .01 ) Gernez et al . , “ Altered phosphorylated signal transducer and acti ( 52 ) U . S . CI. vator of transcription profile of CD4 + CD161 + T cells in asthma: CPC .. .. GOIN 33 / 5091 ( 2013 .01 ) ; GOIN 2333 /52 Modulation by allergic status and oral corticosteroids” , J . Allergy ( 2013 .01 ) ; GOIN 2333 / 70514 ( 2013 .01 ) ; GOIN Clin . Immunol. , Dec . 2007, vol . 120 , No . 6 , pp . 1441 - 1448 . Goodwin et al ., “ Antibody response to influenza vaccination in the 2333 /70517 ( 2013 .01 ) ; GOIN 2333 / 70521 elderly : a quantitative review ” , Vaccine, 2006 , vol . 24 , 1159 - 1167 . ( 2013 .01 ) ; GOIN 2800 /60 ( 2013 .01 ) Hansson , “ Inflammation , Atherosclerosis , and Coronary Artery Dis ( 58 ) Field of Classification Search ease” , The New England Journal of Medicine , Apr. 21, 2005 , vol. None 352 , No . 16 , pp . 1685 - 1695 . See application file for complete search history. ( Continued ) ( 56 ) References Cited Primary Examiner — Pablo S Whaley U . S . PATENT DOCUMENTS ( 74 ) Attorney , Agent, or Firm — KPPB LLP 2001/ 0041362 A1 * 11 / 2001 Taniguchi .. .. CO7K 14 /55 435 /325 (57 ) ABSTRACT FOREIGN PATENT DOCUMENTS Embodiments of the present invention provide diagnostic WO 2006012507 A2 2 / 2006 markers of immunosenescence and methods of identifying WO 2009134944 A2 11 / 2009 individuals with impaired immune function based on a WO 2010006291 A1 1 /2010 combination of such markers obtained from various ana lyzes , primarily from blood , testing immune function includ OTHER PUBLICATIONS ing the analysis of immune cell subset frequencies , gene Hann et al. ( Cellular Signalling , 2005 , 17 : 1542 - 1550 ). * expression , cytokine and chemokine levels , and signaling Wikby et al . (Biogerontology , 2008 , 9 : 299 -308 ) . * responses to stimulation with cytokines (* cytokine Krutzik et al. (Nature Methods, May 2006 ; vol. 3 , Nol. 5 , pp . response ’ ) . Particular combinations of markers can predict 361 - 368 ) . * with high accuracy whether an individual will respond to Ademokun et al ., “ The ageing B cell population : Composition and active vaccination and become protected against recurring function ” , Biogerontology , 2010 , vol . 11 , pp . 125 -137 . diseases. Barrett et al. , “ NCBI GEO : mining tens of millions of expression profiles / database and tools update” , Nucleic Acids Research , 2007 , vol. 35 , Database issue, pp . 760 - 765 . 10 Claims, 36 Drawing Sheets US 10 , 119 ,959 B2 Page 2 ( 56 ) References Cited Shen -Orr et al. , “ Cell type - specific gene expression differences in complex tissues” , Nat Methods , Apr. 2010 , vol . 7 , No. 4 , pp . 287 - 289 . OTHER PUBLICATIONS Hobson et al. , “ The role of serum haemagglutination -inhibiting Shurin et al. , “ Dynamic alteration of soluble serum biomarkers in antibody in protection against challenge infection with influenza A2 healthy aging” , Cytokine , 2007 , vol. 39 , pp . 123 - 129 . and B viruses ” , J . Hyg ., Cambridge , 1972 , vol. 70 , pp . 767 -777 . Southworth et al ., “ Aging Mice Show a Decreasing Correlation of Irish et al. , “ B -cell signaling networks reveal a negative prognostic Gene Expression within Genetic Modules ” , PLoS Genetics , Dec . human lymphoma cell subset that emerges during tumor progres 2009, vol. 5 , Issue 12, 13 pgs. sion ” , PNAS , Jul. 20 , 2010 , vol. 107 , No. 29 , pp . 12747 - 12754 . Storey et al. , “ Statistical significance for genomewide studies ” , Jones et al . , “ Revving the Engine : Signal Transduction Fuels T Cell PNAS , Aug . 5 , 2003 , vol. 100 , No. 16 , pp . 9440 - 9445 . Activation ” , Immunity , Aug . 2007 , vol . 27 , pp . 173 - 178 . Strindhall et al ., “ No Immune Risk Profile Among Individuals who Kirkwood , “ Evolution of ageing ” , Mechanisms of Ageing and Reach 100 years of Age : Findings from the Swedish NONA Development, 200 , vol. 123 , pp . 737 -745 . Krutzik et al. , “ Fluorescent cell barcoding in flow cytometry allows Immune Longitudinal Study” , Experimental Gerontology, 2007 , high - throughput drub screening and signaling profiling " , Nature vol. 42 , No . 8 pp . 753 - 760 . Methods, May 2006 , vol . 3 , No. 5 , pp . 361- 368 . Tusher et al. , " Significance analysis of microarrays applied to the Langfelder et al ., “ WGCNA : an R package for weighted correlation ionizing radiation response” , PNAS , Apr. 24 , 2001 , vol. 98 , No . 9 , network analysis ” , BMC Bioinformatics , 2008 , vol. 9 , 13 pgs . pp. 5116 - 5121. Lifson et al. , “ Variables Affecting T -Lymphocyte Subsets in a Wassel et al ., “ Association of Circulating C - Reactive Prtein and Volunteer Blood Donor Population ” , Clinical Immunology and Interleukin - 6 with Longevity into the 80s and 90s: The Rancho Immunopathology , 1985 , vol. 36 , pp . 151 - 160 . Bernardo Study ” , J . Clin . Endocrinol. Metab . , Oct . 2010 , vol. 95 , Perez et al. , “ Phospho -proteomic immune analysis by flow cytometry : No . 10 , pp . 4748 -4755 . from mechanism to translational medicine at the single - cell level ” , Weiskopf et al. , “ The aging of the immune system ” , European Immunological Reviews, 2006 , vol. 210 , pp . 208 -228 . Society for Organ Transplantation , 2009 , vol. 22 , pp . 1041- 1050 . Potter et al . , “ Determinants of Immunity to Influenza Infection in Weng et al ., “ CD28 - T cells : their role in the age - associated decline Man ” , British Medical Bulletin , 1979 , vol. 35 , No . 1 , pp . 69 -75 . of immune function ” , Trends Immunol. , Jul. 2009 , vol. 30 , No . 1 , Rodwell et al. , " A Transcriptional Profile of Aging in the Human Kidney ” , PLoS Biology , Dec . 2004 , vol . 2 , Issue 12 , 2191 - 2201. pp . 306 - 312 . Rojo et al. , “ Neuroinflammation : Implications for the Pathogenesis Whitney et al. , “ Individuality and variation in gene expression and Molecular Diagnosis of Alzheimer ' s Disease ” , Archives of patterns in human blood ” , PNAS , Feb . 18 , 2003 , vol . 100 , No . 4 , pp . Medical Research , 2008 , vol. 39, pp . 1 - 16 . 1896 - 1901 . Sansoni et al. , “ The immune system in extreme longevity ” , Experi Wikby et al. , “ The immune risk phenotype is associated with IL -6 mental Gerontology , 2008 , vol. 43 , pp . 61 -65 . in the terminal decline stage: Findings from the Swedish NONA Sarup et al. , “ Flies selected for longevity retain a young gene immune longitudinal study of very late life functioning ” , Mecha expression profile ” , Age, 2011 , vol. 33, pp . 69 - 80 . nisms of Ageing and Development, 2006 , vol . 127 , pp . 695 - 704 . Shaw et al. , “ Aging of the innate immune system ” , Current Opinion Witten et al. , “ A penalized matrix decomposition , with applications in Immunology, 2010 , vol. 22, pp . 507 -513 . to sparse principal components and
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