15 Immunodeficiencies

Transcription

1 15 Immunodeficiencies A. Acquired causes of immunodeficiencies 1. Environmental (UV irradiation) 2. Drug induced (immunosuppressants) 3. non-hiv Viral (measles virus) Dr. Andrea Hubbard School of Pharmacy 1 2 Immunodeficiencies: Environmental: UV irradiation Structure and Function of the Skin Layers: Epidermis (most superficial, continually renewing; keratinocytes, LC, melanocytes, Merkel cell) Dermis (fibroblasts, DC, mast cells, collagen, elastin, microvasculature) Subcutaneous (fat) Keratinocytes do not express class II, but do make numerous cytokines as do mast cells in dermis 3 1

2 Langerhans Cells epidermis and dermis Primary APC; highly class II positive 4 Effects of different spectra of UV irradiation UVA minimal biologic activity (melanin) UVB (cell death, DNA damage) UVB also causes sunburn, suntan and vitamin D formation UVC caused skin reddening; germicidal 5 Benefits 6 2

3 Harmful Effects 1. Aging Skin As we age, cell turnover in the epidermis slows and the epidermis becomes thinner. Also, the dermal-epidermal border becomes less undulating. Notice the difference in the thickness of the epidermis between the aged skin slide and the youthful skin slide Ocular Damage 3. Skin Cancer Basal cell, squamous cell carcinoma Melanoma Basal cell carcinoma Melanoma 8 4. Initiate or aggravate photosensitivity especially in patients with SLE, MCTD, etc 5. Photosensitivity in patients on pharmaceutical compounds Brand Name Generic Name Therapeutic Class Motrin ibuprofen NSAID, antiarthritic Crystodigin digitoxin antiarrhythmic Sinequan doxepin antidepressant Cordarone amiodarone antiarrhythmic Bactrim trimethoprim antibiotic Diabinese chlorpropamide antidiabetic (oral) Feldene piroxicam NSAID, antiarthritic Vibramycin doxycycline antibiotic Phenergan promethazine antihistamine 9 3

4 Immunosuppression from high dose UV and low dose UV Immunosuppression by UV irradiation Dependent on wavelength, total UV dose Suppression can be local (suppression achieved if antigen is applied to UV irradiated skin) or systemic (UV applied to one site and hapten to distant non irradiated site) Not dependent upon loss of epidermal LC, or sunburn or skin pigment Low dose UVB irradiation induces inhibition of local sensitization phase of CHS to a hapten applied to previously irradiated skin; no effect on non irradiated skin High dose UVB induces inhibition of the systemic sensitization phase of CHS to hapten and DTH to alloantigen when antigen is injected into distant non irradiated site (probably due to systemic IL-10, TNFα, & T regs) Both kinds of immunosuppression are genetically restricted (at least in mice;? humans) 11 Measured by CHS which is special form of DTH induced by epicutaneous application of low MW haptens (DNFB). In experiments designed to investigate local immune suppression, mice were exposed to UV and a hapten chemical such as dinitrofluorobenzene (DNFB) was applied to the site of irradiation. After an incubation period of several days, animals were challenged by painting the chemical on the ear, and the immune response was assessed by measuring ear thickness, which is an expression of CHS. 12 4

5 13 Initial step is absorption by chromophores (DNA, UCA, melanin) at or near body surface (photoreceptors) DNA damage of keratinocytes (IL-10) Trans to cis isomerisation of urocanic acid (UCA) Membrane changes (oxidative stress & membrane lipid peroxidation) Alteration of LC number, morphology and APC Induce T regs

6 Erythemal doses of UV radiation induce systemic immune suppression by the release of cytokines, soluble mediators, and altered function of antigen presenting cells to induce antigen-specific regulatory T cells Suppression immune response and skin cancer in humans UVR suppresses CHS are termed susceptible (UVS) (35%) No suppression of CHS are termed resistance (UVR) (65%) 92% of non melanoma skin cancer (basal cell, squamous cell) and 100% of malignant melanoma ins UVS group Ullrich SE. Mechanisms Underlying UV induced Immune Responses. Mutation Res 571: (2005) 18 6

7 Immunodeficiencies: 2. Drug induced Organ Transplantation and IS Drugs More donors 19 1 Autologous 20 In selecting donor/recipient matches: 1. Necessary to match blood group proteins 21 7

8 2. Necessary to match HLA proteins (esp A, B and D) HLA-D HLA-A, B or C MHC class I found on nearly every nucleated cell; presents Ag to cytotoxic T cells MHC class II found B cells, macrophages, APC; presents Ag to T helper cells

9 Acute Hyperacute Chronic Acute

10 1 1. Human skin allograft on day 5 (fully vascularized) 2. On day 12 (totally destroyed) 3. Second graft from same donor on day 7 (no vascularization) 28 Acquired Immune Tolerance in the absence of immunosuppressive drugs. 29 Acute rejection Other sides effects from transplantation: Infections Cancer ADE 30 10

11 Induction: corticosteroids anti-thymocyte globulins anti-cd3 anti-il-2r Maintenance: azathioprine mycophenolate cyclosporin tacrolimus sirolimus Treatment of Rejection 31 Cyclosporin Approved by FDA in 1983 for kidney transplants Major adverse effects: fever diarrhea, vomiting, tingling, nephrotoxicity/hepatotoxicity, increased susceptibility to infections, inability to prevent chronic rejection Marketed by Novartis as Sandimmune; Neoral (microemulsion) Mechanism of Action Found to be selective for T lymphocytes Inhibition of proliferation w/o affecting bone marrow cells Prevented T lymphocyte proliferation & activation

12 Approved kidney, liver, heart, lung, heart-lung, bone marrow transplants as well as autoimmune diseases (e.g. psoriasis, atopic dermatitis, RA) 34 Tacrolimus (FK506) In 1984, compound from soil sample taken at foot of Mt. Tsukuba (Tokyo) Streptomyces tsukubaensis Similar to CyA in MOA; more potent immunosuppressive drug In 1986, began clinical trials (Fujisawa Pharm and Univ of Pittsburgh Med. School) In 1990, found efficacy in preventing rejection of liver transplants In 1994, marketed as Prograf and approved by FDA Adverse effects: hyperglycemia, nephrotoxicity, chest pain, etc MOA: Binds FKBP and inhibits calcineurin

13 Tacrolimus approved for liver & kidney transplants; tablets of 0.5,1 or 5 mg Tacrolimus also approved as an ointment in atopic eczema (Elidel (pimecrolimus) Cream and Protopic (tacrolimus) Ointment) 37 Sirolimus (Rapamycin) : MOA Structurally similar to FK506 and binds to FKBP Does not bind calcineurin or inhibit IL-2 Blocks progression through cell cycle Synergistic with CyA 38 Major adverse effects: hyperlipidemia, leukopenia, thrombocytopenia In 1999, approved as immunosuppressive drug by FDA Used in renal transplants; off label for psoriasis Everolimus approved in cancer chemotherapy (RCC) 39 13

14 Rapamycin blocks T and B cells from responding to cytokines and thus prevents progression from the G1 phase (synthesis of RNA and protein) to the S phase (synthesis of DNA). Cell proliferation is therefore inhibited CyA Cyclophilin FK506 FKBP Calcineurin (A) FKBP Rap 42 14

15 43 Immunodeficiencies: 3. non-hiv viral: measles virus (Rubeola) Enveloped, negative-sense, non segmented RNA virus Naturally infects only humans; 1 million deaths worldwide mostly children under age 5 Highly infectious by respiratory route Attenuated virus vaccine (lower titers than natural infection) Natural infection provides life long immunity, but also suppresses immune system increasing susceptibility to secondary infections Immune suppression is coincident with immune system activation and MV specific responses; can continue for several wks Apparent as loss of DTH skin test response, impairment of CMI and HMI, reactivity of TB and remission of autoimmune disease (JRA) Abs in natural infection appears with rash

16 46 Secondary infections: pneumonia, chronic pulmonary disease, otitis media, larynogotracheobronchitis ARDS, hepatitis and diarrhea. Accounts for most of morbidity/mortality in acute measles. Recovery depends on CMI; however MV causes defect in Thelper populations. Mechanism of MV induced immunosuppression o No affect on cytokines (IFNγ, IL-2, IL-6, IL-10) o Defect in component of IL-2 receptor o Elevation in IL-4/decrease in IL-12 which could change Th1:Th2 polarization o MV interaction with its receptor CD46 suppression of IL-12 o Infection of macrophages, not lymphocytes causes apoptosis