ISICR Officers President Howard Young President-Elect INTERNATIONAL SOCIETY FOR Otto Haller INTERFERON AND CYTOKINE RESEARCH Secretary October 2004 Sidney Pestka Volume 11, No. 3 Treasurer Sam Baron The Milstein Award The Milstein Award recognizes individuals who have made excep- Future ISICR Meetings tional contributions to research related to interferons and cytokines either in a basic, translational or clinical field. Milstein awards are Oct. 21-24, 2004 made possible by the generous gift of Mrs. Seymour Milstein and San Juan, Puerto Rico family through the Milstein Foundation. This award represents a (Joint with ICS) pinnacle of scientific achievement in our field and is an important www.cytokines2004.org landmark of the society. * The 2004 Milstein Awardees are: Oct. 20-25, 2005 Shanghai, China Ernest C. Borden, MD Director, Taussig Cancer Center 2006 (Joint ISICR/ICS) Cleveland Clinic Foundation Vienna, Austria Cleveland, OH USA http://www.clevelandclinic.org/cancer/physician/ docs.asp?StaffID=2933 ISICR WWW Site & www.ISICR.org Keiko Ozato, Ph.D. National Institute of Child Health & ISICR Business Office Human Development [email protected] National Institutes of Health TEL: 301-634-7250 Bethesda, MD USA FAX: 301-634-7049 http://dir2.nichd.nih.gov/labs/unit.php3?55 ISICR Newsletter Editors Howard Young The Milstein Young Investigator Awards [email protected] Every year Young Investigator Awards are presented to ISICR Fax: 301-846-1673 members who have made notable contributions to either basic, translational or clinical research within 8 years after receiving Seng-Lai (Thomas) Tan [email protected] their Ph.D or M.D.. This award is provided by a generous gift of the Milstein Foundation. Hannah Nguyen [email protected] (See Milstein Awards, page 2) October, 2004 (Milstein Awards, cont. from page 1) New appointment for ISICR member Larry Pfeffer The 2004 Milstein Young Investigator Awardees are: Chen Dong, Ph.D. Department of Immunology MD Anderson Cancer Center Houston, TX USA Albert S Mellick, Ph.D. Griffith University, Gold Coast Campus The University of Tennessee Health Science Center School of Health Science (UTHSC) is pleased to announce that Mohammad Queensland, Australia Jahanzeb, MD, UT's Van Vleet Professor in Medical Oncology, has been named interim director of the Ehssan Sharif-Askari, Ph.D. UT Cancer Institute and Lawrence Pfeffer, PhD, McGill University/Lady Davis Institute Muirhead Chair of Excellence in Pathology, has been Dept. of Microbiology & Immunology named interim deputy director. Montreal, Canada Dean of the UT College of Medicine, Henry G. Tomohiko Tamura, MD, Ph.D. Herrod, MD, commented, "We are excited to have National Institute of Child Health & Human these two individuals officially named as part of the Development UT Cancer Institute's leadership team. As we begin National Institutes of Health building the basic science facility in December of Bethesda, MD USA this year and expanding research opportunities, their expertise and leadership will play a key role in mov- ing the institute forward." The Christina Fleischmann Memorial Award to Young Women Investigators Dr. Pfeffer is vice chair and director of the graduate Every year the Christina Fleischmann Memorial program in pathology, as well as director of basic Award is presented to a young woman ISICR mem- research for the Cancer Institute. In his new posi- ber who has made notable contributions to either tion, he will be assuming a more direct role in basic, translational or clinical research within 10 organizing and directing the research initiatives years after receiving their Ph.D or M.D. This award within the Cancer Institute. is made possible through the generosity of the Fleischmann Foundation and is dedicated to the Dr. Pfeffer joined UT in 1991 after moving here memory of ISICR member and outstanding interfer- from New York where he was a faculty member at on research scientist Christina Fleischmann. the Rockefeller University for twelve years. He received a doctorate degree from Sloan-Kettering The 2004 Christina Fleischmann Awardee is: Division of the Cornell University Graduate School of Medical Sciences and was a postdoctoral research Brenda L. Fredericksen, Ph.D. fellow at Rockefeller University. University of Texas Southwestern Medical Center Department of Microbiology Dallas, TX USA 2 International Society for Interferon and Cytokine Research Perspective: Cytokine Gene treatment strategies in the clinic. Of note, the stratifi- Polymorphisms in Human Diseases cation of information is helping researchers to identi- Venky Ramakrishna PhD, Medarex, Inc., NJ fy responders and non-responders in clinical trials not only to streamline accrual of 'likely-to-benefit' patients but also to intervene in the event of an unde- sired clinical outcome in affected patients. This review will briefly discuss the overall impact that these studies are likely to have on establishing new guidelines and benchmarks needed to achieve effec- tive clinical management of diseases. 1. Introduction 2. Degree of cytokine gene polymorphism Genes that regulate products involved in immunity The vast majority of polymorphisms seen among are highly polymorphic and contribute to inter-indi- cytokines and cytokine receptors are thought to arise vidual differences that can influence the final out- from the non-translated regions of the genes. While come of antigen-specific and non-specific responses. most cytokines have corresponding receptors, there These products broadly fall under two main cate- are a few (TNFα, IL-1) that have multiple receptors. gories of cytokines: pro-inflammatory or T-helper 1 The increase in the number of novel cytokine poly- (T 1 - IL-2, IFNγ, IL-12, TNFα) and anti-inflamma- H morphisms that have been reported to date have been tory or T-helper 2 (T 2 - IL-4, IL-5, IL-10), and are H aided, in large part, by the availability of sophisticat- produced in response to specific and non-specific ed technologies (TaqMan PCR, RFLP, SSCP, reverse stimuli in cancer, infectious disease and autoimmune SSOP, ARMS, dsDNA, RSCA, and oligonucleotide pathologies. While a T 1 cytokine profile supports H microarray) and sequence databases that permit the development of a cytotoxic T lymphocyte (CTL) analysis of larger gene segments controlling cytokine and a delayed-type hypersensitivity (DTH) response, production. The high volume and high throughput a T 2 profile will typically induce a humoral H features of these technologies now enables response (antibody production via B-cell activation) [1-2]. There are several different cytokines produced researchers to extend their window of analyses from by other cells of the immune system (macrophages, 2 kb up to nearly 8 kb in their 5' promoter regions monocytes, neutrophils, mast cells, keratinocytes, and also to discover single nucleotide polymor- dendritic cells etc.) that can either synergize with or phisms (SNPs) in cytokines previously shown to be non-polymorphic (IL-2, IL-6, IL-6R, IL-8, IL-12 and antagonize a TH1 or TH2 response. Monitoring the dif- ferent types of cytokines produced and the analysis IL-18; reviewed in Ref. 3). The extent of polymor- of cytokine receptor genes has, as a result, gained phism known about a gene is, therefore only limited importance not only from the standpoint of under- by the sophistication of the research tool used. The standing the etiology of the disease but also for most comprehensive document on cytokine gene potential better management of patients undergoing polymorphisms is available as online databases therapy. [www.pam.bris.ac.uk/services/GAI/cytokine4.htm However, the rationale for establishing the link and Ref. 3]. between cytokine gene polymorphisms and suscepti- bility to human diseases stemmed from the genuine 3. Influence of polymorphism on cytokine need to understand the causes and the etiological as production well as pathological basis of the disease. These The induction and release of pro-inflammatory or efforts have essentially contributed to the identifica- anti-inflammatory cytokines is crucial to the mainte- tion of biomarkers that underscore not only predispo- nance of immune homeostasis i.e. regulating the bal- sition to development of the disease but also predict ance between immune activation (Th1) versus its severity and clinical outcome. In the process, immune suppression (Th2). This obviously raises the potential targets for therapeutic intervention have question of whether individuals with genetic poly- been identified that form the basis of designing smart morphisms for cytokine genes vary in their ability October, 2004 3 (Ramakrishna, cont. from page 3) imal or irrelevant [4-5]. As a result, the assessment of true impact of ethnicity on cytokine polymor- to produce cytokines and whether there is a link with phisms and disease susceptibility may be under- their susceptibility to disease. Polymorphisms found mined by small differences in the estimates that can in the 5' or 3' regulatory sequences can alter binding have a tighter association, primarily by mismatch sites of transcription factors and thereby decrease or rather than disease susceptibility. Therefore, new shut down transcription or alter promoter activity. benchmarks are needed in designing high impact dis- Other polymorphisms found in the intronic sequences ease association studies, especially in the United can affect mRNA splicing or cause structural anom- States where large ethnic populations are localized in alies in enhancers and silencers. Conservative muta-