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Wo 2008/021431 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date PCT 21 February 2008 (21.02.2008) WO 2008/021431 A2 (51) International Patent Classification: (74) Agents: WARD, Michael, R. et al.; Morrison & Foerster C12Q 1/68 (2006.01) LLP, 425 Market Street, San Francisco, CA 94105-2482 (US). (21) International Application Number: PCT/US2007/018135 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: 14 August 2007 (14.08.2007) AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, (25) Filing Language: English ES, FT, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, (26) Publication Language: English MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, (30) Priority Data: TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, 60/837,698 14 August 2006 (14.08.2006) US ZM, ZW (71) Applicant (for all designated States except US): EXPRES¬ (84) Designated States (unless otherwise indicated, for every SION DIAGNOSTICS, INC. [US/US]; 3260 Bayshore kind of regional protection available): ARIPO (BW, GH, Blvd., Brisbane, CA 94005 (US). GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), (72) Inventors; and European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (75) Inventors/Applicants (for US only): ROSENBERG, FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, PL, Steven [US/US]; 2323 Bywood Drive, Oakland, CA PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, 94602-2012 (US). FRY, Kirk [US/US]; 2604 Ross Road, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). Palo Alto, CA 94303 (US). WU, Bin [US/US]; 1125 Ranchero Way, Apt. #35, San Jose, CA 951 17 (US). Published: DEDRICK, Russell, L. [US/US]; 25 Westminster Av — without international search report and to be republished enue, Kensington, CA 94708 (US). upon receipt of that report (54) Title: METHODS AND COMPOSITIONS FOR DIAGNOSING AND MONITORING THE STATUS OF TRANSPLANT REJECTION AND IMMUNE DISORDERS (57) Abstract: The invention presents methods of using splice variants and reagents thereof for diagnosing and monitoring the status of transplants and immune disorders including diagnosing, monitoring and predicting transplant rejection or non-rejection, steroid responsiveness, and onset or flare of immune disorders. METHODS AND COMPOSITIONS FOR DIAGNOSING AND MONITORING THE STATUS OF TRANSPLANT REJECTION AND IMMUNE DISORDERS RELATED APPLICATIONS [0001] This application claims benefit of US Provisional Application Serial No. 60/837,698, filed August 14, 2006, which is incorporated herein by reference in its entirety. TECHNICAL FIELD 10002] The invention relates to methods and materials involved in diagnosing and monitoring the status of transplant rejection and immune disorders by using splice variants to improve the assessment of immunological or inflammatory activity in subject samples. BACKGROUND OF THE INVENTION [0003] The human immune system plays a defensive role in most immunological conditions, diseases, and disorders. However, it can also function adversely when cells, tissues, or organs are transplanted from one individual to another by attacking these allografts. In addition, certain autoimmune diseases are caused by inappropriate immune system response, where the immune system attacks the body's own cells, tissues, or organs. Thus, it is necessary to modulate immune response when a patient receives a transplant or suffers from an immune disorder, especially during the onset or flare of such disorders. Such modulation can involve changing or varying the amount of immunosuppressive drugs, usually steroids, administered to an individual in need of immunosuppression. After transplant or suppression of a flare, the dosage of immunosuppressant(s) is reduced as quickly as possible to prevent side effects and to preserve some immune response against infectious or opportunistic diseases. [0004] In the months and/or years after transplant or onset of an immune disorder, the individual is usually monitored for tissue damage, dysfunction, or graft rejection. In heart transplant, for example, the heart muscle is biopsied by a surgeon and evaluated by a pathologist at least once a month for a year or more. Each biopsy is invasive, painful, and expensive; moreover, the biopsy is extremely localized, and histological abnormalities in any non-biopsied area of the heart are easily missed. In immune disorders and other transplants, biopsy and/or other assays are performed to detect changes in gene expression, metabolites, or proteins and to monitor the subject's immune response. [0005] The role of leukocytes in immune disorders, especially rheumatic disorders such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), has become the focus of a great deal of research. These two diseases are both characterized by dysregulation of the immune system (causing damage to a variety of tissues and organs) and differential expression of genes in leukocytes (e.g., B- cells, granulocytes, monocytes, and T-cells) suggesting the use of these differentially expressed genes in diagnosing and monitoring immune disorders. However, definitive diagnosis and prediction of flares remain challenging despite recent advances in gene expression profiling (Baechler et al (2003) PNAS 100:2610-2615, Kirou et al (2004) Arthritis and Rheumatism 50:3958-3967, and Kirou (2005) Arthritis and Rheumatism 52:1491-1503). [0006] While expression of a single gene can often be correlated with normal or abnormal function or status, the simultaneous measurement of differential expression in several genes greatly increases accuracy for detecting transplant rejection, steroid responsiveness, and disease activity. Furthermore, assaying gene expression in blood samples is far more comprehensive and less invasive than biopsy in determining transplant rejection (cf. Deng et al (2006) Am J Transplant 6:150-160) or diagnosing and monitoring the status of transplants and immune disorders. [0007] There is a need in the art for improved diagnosis and monitoring of the status of transplants and immune disorders, especially transplant rejection or non- rejection, steroid responsiveness, and onset or flare of immune disorders. Preferred methods would utilize blood samples to further improve over existing techniques. The present invention provides methods for using splice variants of genes known to have utility in diagnosing and monitoring the status of transplants and immune disorders to improve diagnosis and monitoring of transplant rejection, steroid responsiveness, and onset or flare of immune disorders. SUMMARY [0008] The invention presents methods for using splice variants of genes known to detect transplant rejection or to diagnose immune disorders to improve diagnosis and monitoring of the status of transplant rejection or immune disorders. The invention also presents the use of splice variants, primers, primer sets, probes, amplicons, antibodies and affinity reagents that specifically detect the expression of the splice variant using nucleic acid and protein technologies, assays and diagnostic kits. [0009] One aspect of the present invention is a method for diagnosing or monitoring the status of a transplant or an immune disorder by selecting a splice variant of a gene where the gene is known to have utility in diagnosing or monitoring the status of a transplant or immune disorder; detecting expression of the splice variant using a probe that specifically detects the expression of the splice variant; and diagnosing the status of a transplant or immune disorder based on the expression of the splice variant in the sample. [0010] In certain embodiments of the method, transplant rejection or non-rejection in a patient and/or onset or flare of the immune disorder in a subject are diagnosed and monitored, efficacy of a therapeutic agent is determined, treatment administered to one or more patients with a transplant or subjects with an immune disorder is monitored, steroid or immunosuppressant responsiveness of one or more patients with a transplant or subjects with an immune disorder is assessed, a treatment plan for a patient with a transplant or a subject with an immune disorder is monitored, T cell activity is monitored, or acute cellular rejection is monitored. [0011] In a second embodiment of the method, the probe is a primer or a primer set that specifically detects expression of the splice variant by generating an amplicon of the splice variant in a polymerase chain reaction (PCR). In a third embodiment, the probe is an antibody or affinity reagent that specifically detects expression of the splice variant by specifically binding an epitope of the splice variant. In a fourth embodiment, the splice variant encodes polypeptides such as ADM, CBLB, CD44, CXCR3, CXCR4, FASL, FLT3, G6B-1, ILl R2, ITGA4, ITGAM, ITGB7, LAIR2, MARCH8, OAS3, PDCDl, PRDM, PF4, RHOU, SEMA7A, WDR40A or ZNFNlAl or fragments thereof. In preferred embodiments, the splice variants are CD44vl-lN, IL1R2V4-7N, LAIR2v2-2N, and PRDMW1-2N. In a fifth embodiment, the transplant being monitored is an allograft of an artificial organ, a mechanical organ, bone marrow, a cornea, a heart,
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