We live in a dangerous world:“New” Infectious Agents/Diseases Identified Since 1975.

1. We live in a dangerous world:“New” Infectious Agents/Diseases Identified Since 1975. 1976 Cryptosporidium parvum (Cryptosporidiosis) 1976 Legionella (Legionnaire’s Disease) 1976 Ebola Virus (Ebola) 1982 E. coli O157 (lethal food poisoning) 1982 Borrelia burgdorferi (Lyme Disease) 1983 HIV (AIDS) 1983 Helicobacter pylori (peptic ulcers) 1989 Hepatitis C (nonA-nonB Hepatitis) 1992 Vibrio cholerae 0139 (new, virulent serotype of Cholera) 1993 Four Corners/Sin Nombre Virus (Hantavirus Pulmonary Syndrome) 1995 Human Herpesvirus 8 (Kaposi’s Sarcoma) 1996 Prions (variant Creutzfeld-Jacob Disease = “Mad Cow” in humans) 1997 H5N1 Influenza virus (Direct bird to human, super-virulent Flu) • West Nile Virus (in N. America - Encephalitis) 2003 SARS coronavirus (SARS)

2. Not to mention those diseases that have been around for a while(Leading causes of death globally) Rank % of total 12.7 9.9 7.1 4.8 4.8 4.2 4.0 3.0 1.9 • 1 Ischaemic heart disease • 2 Cerebrovascular disease • 3 Acute lower respiratory infections • 4 HIV/AIDS • 5 Chronic obstructive pulmonary disease • 6 Perinatal conditions • 7 Diarrhoeal diseases • 8 Tuberculosis • 11 Malaria Source: The World Health Report 2000, WHO

3. White Blood cells: The home team

4. Innate Immune system (used by most multicellular organisms) • First line of defense against invading microbes • Various blood cells have special “Toll-like Receptors’ or TLRs on their surface which recognize common microbial molecules • When these receptors are activated they cause the cells bearing them to release soluble factors which dialate local blood vessels (inflammation) and attract other blood cells to migrate to that site.

5. Adaptive Immunity(almost all vertebrates) • Antibodies and T Cell Receptors:A unique class of proteins which give lymphocytes a very large repertoire of potential anti-microbial reagents, even to ones that are completely new or synthetic. • These are expressed clonally (one per cell) allowing the rapid expansion of just those cells which are specific for a particular microbe. • Some of these lymphocytes become “memory cells” which can persist for 50 or more years, giving long-lasting immunity (which is why vaccines work).

6. The generation of Immunoglobulin and T cell receptor diversity taken from Immunobiology, Janeway and Travers

7. Stanford as the World leader in development of Immune Monitoring technologies • !970’s FACS technology • 1983 CD4/CD8 ratio in AIDS • 1996 peptide/MHC tetramers • 2002 Autoantigen arrays • 2002 Phospho Flow analysis • 2003/5 Cellular arrays

8. Lymphocyte antigen recognition B CELLS T CELLS

9. T cells recognize “pieces” of antigens

10. 1 pMHC: 5 µm 1 pMHC: 5 µm

11. But as remarkable as the immune system is, the downside is that it often turns against the body’s own tissues, resulting in autoimmunity or allergies.

12. Allergic Rhinitis • Alopecia Areata • Amyloidosis (and subtypes) • Anaphylaxis/environmental exposure • Ankylosing Spondylitis • Antiphospholipid Syndrome • Asthma • Atopic dermatitis • Autoimmune Hearing Loss • Autoimmune Hemolytic Anemia • Autoimmune Hepatitis • Autoimmune thrombocytopenic purpura • Cardiomyopathy • Celiac Sprue-Dermatitis • Chronic Fatigue (CFIDS) • Chronic Inflammatory Demyelinating Polyneuropathy • CREST Syndrome • Crohn's Disease • Dermatitis herpetiformis • Diabetes Type I • Discoid Lupus • Eosinophilic Pneumonia • Epidermolysis bullosa acquisita • Erythema Nodosum • Essential Mixed Cryoglobulinemia • Familial Mediterranean Fever • Glomerulonephritis • Goodpasture's Syndrome • Gout and crystal arthitidies • Graft-versus-host disease in BMT • Graves' Disease • Guillain-Barré • Hashimoto's Thyroiditis • Hypersensitivity Pneumonitis • Idiopathic Pulmonary Fibrosis • IgA Nephropathy • IgA Linear Dermatosis • Immune-mediated infertility • Inflammatory Bowel Disease • Juvenile Arthritis • Lambert-Eaton Myasthenic Syndrome • Lichen Planus • Ménière's Disease • Mixed Connective Tissue Disease • Multiple Sclerosis • Myasthenia Gravis • Myocarditis • Neutrophilic Dermatoses (Sweet's) • Osteoarthritis • Pemphigoid (Bullous) • Pemphigus foliaceus • Pemphigus Vulgaris • Pernicious anemia • Polychondritis • Polyglandular Syndromes • Polymyalgia Rheumatica • Polymyositis and Dermatomyositis • Primary Biliary Cirrhosis • Psoriasis • Psoriatic arthritis • Pyoderma gangrenosum • Raynaud's Phenomenon • Reflex Sympathetic Dystrophy • Reiter's Syndrome • Rheumatic Fever • Rheumatoid Arthritis • Sarcoidosis • Scleroderma • Sclerosing cholangitis • Sjögren's Syndrome • SLE • Solid Organ Transplant rejection • Stevens Johnson syndrome • Sympathetic ophthalmia • TTP/HUS • Ulcerative Colitis • Urticaria • Uveitis • Vitiligo • Vasculitis • ANCA Positive Vasculitis • Wegener's • Giant cell • PAN • Takayasu's • Henoch Schoenlein • Churg-Strauss • Kawasaki's • Hypersensitivity • Behcet's • Thromboangiitis obliterans • Total: • 90 Autoimmune • Diseases

13. Or fails to mount a vigorous defense against cancerous cells or microbes which disable key parts

14. It is also not as effective in the very young or in older people

15. In organ transplants, current therapy is to heavily suppress the T cell immune response, but this then weakens the recipient with respect to infectious diseases and cancer

16. The Immunological Spectrum Autoimmunity Disease prone Allergy Healthy Overactive Underactive

17. Where does the future lie in using what we now know about the Immune System to advance human health? • Traditionally, these diseases and treatments have been handled by many different medical specialties and clinics. • While this has generally worked well (and Stanford has led the way in many of these areas) it is now time for a more integrated approach- as embodied in the Stanford Institutes of Medicine…

18. The Institute for Immunity, Transplantation and Infection at Stanford

19. The ITI Mission • Build translational research that leverages decades of major contributions in immunology, transplantation, microbiology and infectious diseases • Facilitate translation by integrating Basic research about immune-mediated and infectious processes in human disease Clinical research about disease processes and methods to detect, prevent and treat immune-mediated and infectious diseases • Create innovative programs in global infectious diseases that address these causes of the worldwide crisis in human health • Enhance educational opportunities for students at all levels • Mark M. Davis Ph.D., Director • Carlos Esquivel. M.D., Ph.D. Associate Director • 300+ Stanford Faculty

20. Interdisciplinary teams to attack diseases “from soup to nuts” • Rheumatoid Arthritis • Lupus • Juvenile Diabetes • Hepatitis C • TB • HHV-6/ Chronic Fatigue Syndrome • Immune tolerance to transplanted organs/tissues

21. The Human Immune Monitoring Center at Stanford (D. Hirschberg, Director) In this facility we will take advantage of new technologies, many developed here, to get a rapid and comprehensive picture of a patient’s immune system and response to therapy (we gratefully acknowledge support from the HEDCO foundation, theSidney E. Frank foundation and from Becton Dickenson Corp)

22. Stanford as the World leader in development of Immune Monitoring technologies • !970’s FACS technology • 1983 CD4/CD8 ratio in AIDS • 1996 peptide/MHC tetramers • 2002 Autoantigen arrays • 2002 Phospho Flow analysis • 2003/5 Cellular arrays

23. Affymetrix GeneChip arrays and other devices can collect masses of data from small samples • 25mer oligonucleotides • Synthesised directly on a glass substrate (photolithography) • Each chip divided into ~32 000 “features”, each containing a single oligo.

24. The Immunological Spectrum Autoimmunity Disease prone Allergy Healthy Overactive Underactive

25. The medicine of the future should incorporate key indicators of each person’s immunological health and disease history This could provide early warning signs of risk factors for diseases on either end of the immunological spectrum as well as a better understanding of the underlying causes

26. What to do to help your immune system work better? • NOW • Good nutrition (Zinc effect) • Exercise (recent Tai Chi paper!) • FUTURE • More data/ immune monitoring • New immune stimulants in the pipeline

27. Stanford vaccine studies • The Ellison Foundation is supporting a study of the immune response to a flu vaccine (MMD). • This will use the new Human Immune Monitoring Center to try and pinpoint specific immune defects in older people. • Standby for enrollment opportunities!