Chapter 17 AIDS and secondary immunodeficiency

1. Chapter 17 AIDS and secondary immunodeficiency Trai-Ming Yeh, Ph.D. Department of Medical Laboratory Science and Biotechnology College of Medicine National Cheng Kung University

2. Secondary (acquired) immunodeficiency • Primary vs. acquired immunodeficiency • Acquired immunodeficiency • Immunosuppressive drugs immune enhancement • Corticosteroids • Cytotoxic immunosuppressants • Fungal and bacterial derivatives • Monoclonal antibodies • Malnutrition-induced immunodeficiency • Infection-induced immunodeficiency • HIV

3. Anti-inflammatory drugs • 例子 • Prednisone modified from cortisol • 應用 • Transplantation • Autoimmune disease • Allergic disease • 副作用 • Fluid retention, weight gain, diabetes, bone mineral loss, thinning of the skin 和cytotoxic drug 一起使用

4. Corticosteroids bind to their intracellular receptors and regulate gene expression

5. Genes affected by steroid • Function • 減少inflammatory mediator的製造 • 使adhesion molecules表現下降 • Endonuclease製造上升

6. Neutrophilia, lymphocytopenia, monocytopenia • T cell activation and B cell maturation are inhibited • Cytokine synthesis is inhibited

7. Cytotoxic immunosuppressants 和IMP競爭DNA合成所需酵素 Azathioprine (cytostatic) Mycophenolate (inhibits de-novo purine biosynthesis) DNA covalent alkylation Cyclophosphamide (cytotoxic)

8. Cytotoxic drugs • Methotrexate blocks DNA synthesis • leflunomide is converted to A77 1726 which inhibits dihydro-orotate dehydrogenase, an enzyme required for pyrimidine nucleotide synthesis • 副作用 • Leukopenia, thrombocytopenia, intestinal epithelium injury, hair loss, fetal death • 應用 • Eliminate unwanted immune responses • Eliminate all dividing lymphocyte : high dose

9. Fungal and bacterial derivatives • 機制 • 干擾T cell的訊息傳遞 • 和immunophilins（一種胞內蛋白）結合，干擾對T cell增生重要之訊息途徑 • 例子 • Ciclosporin (Cyclosporin A) : Tolypocladium inflatum • FK506 (tacrolimus) : Streptomyces tsukabaensis • Rapamycin : Streptomyces hygroscopicus

10. Cyclosporin A & FK506 • 應用： • Prevent allogenic graft rejection：能抑制對特定抗原產生反應的T cell之增生 • 手術時：高劑量 • 手術後：劑量降低 • 缺點 • 對其它器官的傷害（eg. kidney和T cell有相同的target)

11. Cyclosporin A & FK506

12. Cyclosporin A FK506 (tacrolimus) • 機制 • 使calcineurin的phosphotase活性受抑制，進而使T cell增生受抑制 • Cyclosporin A + cyclophilins • FK506 + FKBP

14. 磷酸化（抑制活性） Rapamycin- immunophilin Rapamycin • 機制：rapamycin-immunophilin block signal transduction pathway of IL-2 receptor but not T cell activation, cause G1 arrest p70S6 kinase 調控蛋白質 之轉譯 磷酸化 mTOR PHAS-1 （repressor) 活性下降 磷酸化

17. NUTRIENT DEFICIENCIES ARE GENERALLY ASSOCIATED WITH IMPAIRED IMMUNE RESPONSES • Infection and malnutrition usually aggravate each other • Lymphoid tissues are damaged by nutrient deficiencies • Protein-energy malnutrition affects cell-mediated immunity and phagocytosis • Zinc and iron deficiencies have a variety of effects on immunity • Selenium and copper are also important for immune responses • Vitamin supplementation is of value in severe measles • Vitamin A deficiency • Vitamin B6 and folate deficiencies • Obesity is associated with altered immune responses • Some nutrients in moderate excess enhance immune responses • vitamin E; vitamin A; zinc; and selenium • Probiotics benefit health and immunity

18. ACQUIRED IMMUNE DEFICIENCY SYNDROME(AIDS) • The most significant global cause of immunodeficiency is HIV infection • CD4 antigen is the main receptor for HIV entry: The viral envelope glycoprotein gp120 binds to CD4 • Immune dysfunction results from the direct effects of HIV and impairment of CD4 T cells • Antibody response appears to be ineffective in controlling HIV infection • Cellular immune responses play a role in controlling HIV viremia • HIV-1-specific CTLs in chronic progressive HIV-1 infection are impaired • HIV-1-specific CD4 T cells are preferentially infected by the virus

20. Acute HIV infection is associated with a transient depletion of peripheral CD4 T cells AIDS is defined by a CD4 count < 200/μl

21. Seroconversion: Antibody against HIV positive

22. The most significant global cause of immunodeficiency is HIV infection • CD4 antigen is the main receptor for HIV entry: The viral envelope glycoprotein gp120 binds to CD4 • Immune dysfunction results from the direct effects of HIV and impairment of CD4 T cells • Antibody response appears to be ineffective in controlling HIV infection • Cellular immune responses play a role in controlling HIV viremia • HIV-1-specific CTLs in chronic progressive HIV-1 infection are impaired • HIV-1-specific CD4 T cells are preferentially infected by the virus

23. More severe infections are associated with a low CD4 count • Kaposi's sarcoma: Infection with human herpes virus 8 (HHV8) • Pneumonia is common and Pneumocystis carinii is the commonest infection (see Fig. 17.6), but bacterial infections, including Mycobacterium tuberculosis, and fungal infections also occur. • candidiasis (thrush),diarrhea and weight loss (see Fig. 17.6) • Toxoplasmosis, a protozoal infection, causes cysts in the brain and neurological deficit (see Fig. 17.6). • Cryptococcus neoformans is a fungus that causes meningitis.

24. Treatment with highly active antiretroviral therapy (HAART) controls HIV infection • zidovudine (AZT) was licensed as the first nucleoside analog reverse transcriptase inhibitor (NRTI) • non-nucleoside reverse transcriptase inhibitors (NNRTIs) • protease inhibitors • entry inhibitors • Combination chemotherapy (HAART): two NRTIs; and a NNRTI or protease inhibitor.

25. HIV vaccine • An effective vaccine remains an elusive goal

26. 99.12.2, 中國時報 疾病管制局2010年10月底統計資料顯示，累積本國籍通報為愛滋病毒感染者計1萬9735例，依感染危險因素分析，性行為佔65.5%（未具防護的男性間性行為佔43.4%、異性間性行為佔22.1%）。其次為共用針具與稀釋液佔32.6%，顯見行為才是主因。感染者年齡則以20至29歲最多，佔38.1%，其次為30至39歲，佔35.2 %。特別要注意的是，年輕族群（15- 24歲）感染愛滋近年來有逐漸增加的趨勢。年輕族群在2007年佔總通報人數的14%（272例）、2008年佔20%（351例），到2009年更上升至28%（413例）。值得重視的是，年輕族群90%都是性行為傳染。因此不論是男性或女性、同性戀或異性戀，以及職業類別，只如果從事不戴保險套防護的性行為、與性交往史不明對象間的性行為，以及共用針具與稀釋液等，都可以感染上愛滋病毒。12月1日是世界愛滋日，根據世界衛生組織建議，使用保險套可以有效阻隔體液（精液、陰道分泌物或血液）進入人體，將感染愛滋與性病的機率降到最低。只要全程正確使用保險套，不沾染毒品，就能杜絕愛滋感染。 愛滋病空窗期約是愛滋病毒感染後6-12週內，民眾勿以捐血方式來篩檢愛滋病毒，除危及用血者的安全外，亦可能因此觸法，若有需要可至愛滋病指定醫院進行篩檢，懷疑自己可能感染愛滋病毒，但又擔心檢驗後身份曝光而不敢接受檢驗的民眾，則可至衛生署疾病管制局委託愛滋病指定醫院設立之免費匿名的篩檢諮詢管道進行篩檢，政府有一個全民「認識愛滋、支持篩檢、及早治療」，請說明愛滋篩檢的免疫原理。

27. Chapter 18 Vaccination Trai-Ming Yeh, Ph.D. Department of Medical Laboratory Science and Biotechnology College of Medicine National Cheng Kung University

28. Summary of Chapter 18 Vaccination • Vaccination applies immunological principles to human health. • A wide range of antigen preparations are in use as vaccines. • Adjuvants enhance antibody production. • Most vaccines are still given by injection. • Vaccine efficacy needs to be reviewed from time to time. • Vaccine safety is an overriding consideration. • Vaccines in general use have variable success rates. • Passive immunization can be life-saving. • Non-specific immunotherapy can boost immune activity. • Immunization against a variety of non-infectious conditions is being investigated.

29. Vaccines have two major effects- Individuals and herd immunity

30. A WIDE RANGE OF ANTIGEN PREPARATIONS ARE IN USE AS VACCINES

31. Live vaccines can be natural (rare) or attenuated organisms

32. Attenuated live vaccines have been highly successful • ATTENUATED MICROORGANISMS ARE LESS ABLE TO CAUSE DISEASE IN THEIR NATURAL HOST • VACCINIA VIRUS IS BEING USED AS A VECTOR FOR ANTIGENS OF MICROORGANISMS SUCH AS HIV AND MALARIA

33. Killed vaccines are intact but non-living organisms

34. Inactivated toxins and toxoids are the most successful bacterial vaccines

35. Subunit vaccines and carriers

36. Adjuvants enhance antibody produciton by concentrate antigen at appropriate sites or induce cytokines

37. Anti-idiotype vaccines could be used when the original antigen was unsuitable

38. Induction of appropriate immunity depends on the properties of the antigen

39. VACCINE SAFETY IS AN OVERRIDING CONSIDERATION

40. VACCINES IN GENERAL USE HAVE VARIABLE SUCCESS RATES

43. Vaccines for parasitic and some other infections are only experimental

44. PASSIVE IMMUNIZATION CAN BE LIFE-SAVING

45. NON-SPECIFIC IMMUNOTHERAPY CAN BOOST IMMUNE ACTIVITY

46. 注射新H1N1疫苗後後的局部不良反應包括發紅、疼痛、腫脹、瘀血等，另有些人有全身性不良反應包括鼻塞、發燒、肌肉酸痛、頭痛、噁心、嘔吐，如果對疫苗的成份如雞蛋的成份過敏，甚至會引發全身性的休克反應。國內注射新流感疫苗發生一般的輕微的不良反應的比率與國外相似。但2010年H1N1流行時有一位七歲男童接種國光的新流趕疫苗後，隔天出現紅疹、發燒等症狀，先後住院治療，但仍在注射新流感疫苗後40天後死於敗血症，這位男童有『全身性幼年性類風濕關節炎』的病史，因此事件引起對新流感疫苗是否安全的疑慮，也造成國人接種意願的降低，請您免疫學的觀點評論此事。注射新H1N1疫苗後後的局部不良反應包括發紅、疼痛、腫脹、瘀血等，另有些人有全身性不良反應包括鼻塞、發燒、肌肉酸痛、頭痛、噁心、嘔吐，如果對疫苗的成份如雞蛋的成份過敏，甚至會引發全身性的休克反應。國內注射新流感疫苗發生一般的輕微的不良反應的比率與國外相似。但2010年H1N1流行時有一位七歲男童接種國光的新流趕疫苗後，隔天出現紅疹、發燒等症狀，先後住院治療，但仍在注射新流感疫苗後40天後死於敗血症，這位男童有『全身性幼年性類風濕關節炎』的病史，因此事件引起對新流感疫苗是否安全的疑慮，也造成國人接種意願的降低，請您免疫學的觀點評論此事。

47. IMMUNIZATION AGAINST A VARIETY OF NON-INFECTIOUS CONDITIONS IS BEING INVESTIGATED (tumor vaccine?) • Future vaccines will use genes and vectors to deliver antigens • Vaccinia is a convenient vector • BCG and salmonellae have been favored for experimental recombinant bacterial vaccines • Transgenic plants can be genetically engineered to express vaccine antigens • A recent development is the use of ‘naked’ DNA (gene gun)(without needle injection)

48. bUDR: bromodeoxyuridine Thymidine analog TK: thymidine kinase

49. Important points needed to understand after class • How does HIV infection cause AIDS? • The role of vaccine in preventive medicine. • The development and use of vaccine.