General Topics

Antihistamines Prevent histamine from binding H-1 histamine receptors on endothelium and SM. Histamine can=t increase permeability. Pg 287

Epinephrine Stimulates reformation of tight junctions in endothelial walls (reduces permeability, fluid loss and edema). Relaxes smooth muscle. Pg. 283

Corticosteroids Prednisone. Effects Mφ / t cell interaction. Mainstay of rejection therapy. IL 1,3,4,5,8, TNFα and GM-CSF inflammationNOS NOPhospholipase A2 Prostoglandin and leukotrienes (inflammation)Adhesion molecules Migration of immune cell to site of transplant

Fk506 (Tacrolimus) inhibits IL2 gene transcription Conjugated with FKBP it blocks NFAT site on Calcineurin pg 351

Cyclosporin Interferes w/IL2 synthesis Conjugated with CyP (cyclophilin) it blocks NFAT site on calcineurin. pg. 351

Rapamycin inhibits IL2/receptor signaling Binds FKBP like fk506 but inhibits during signal transduction pg. 352

OKT3, ALG, ATG Anti lymphocyte antibodies. Human lymphocytes given to animal that produces antibodies for human immune cells. Antibodies then given to humans to suppress immune system. ALG=anti-lymphocyte Globulin ATG= anti thymocyte globulin

CTLA-4, CTLA-4-Ig New Immunosupression Therapy. Blocks activation of T cells. Inhibits CD28-B7 interaction

Dr. Noben-Traugh’s Lectures

1. Viruses: T cells, CD8Intra. Bacteria: CD8Extr. Bacteria: TH2, CD4Parasites: CD4, CD8, eosinophils, and B cellsFungi:

2. Know the role played by interferon, complement and inflammatory cytokines in the anti-microbial response.

Inflammatory Cytokine (see page 212, diagram 8.10)IL1, IL6, IL8, IL12, TNFα

Pyrogenic: IL1, IL6, TNFα

Interferon IFN-α, IFN-β and IFN-γBlock the spread of virus to uninfected cells. The expression of these interferons is induced by double stranded viral RNA.

Mode of action: a. prevent replication of virus within infected cellsb. prevent spread of virus to uninfected cellsc. activate innate and adaptive immune response that target the virus-infected cells. They increase the presentation of MHC class I molecules to CD8 T cells.

Complement Infection = ↑C3 hydrolysis-C3 (H20) binds to B, B can be cleaved by D = C3(H20)Bb (C3 fluid convertasae)-C3 convertase cleaves more C3 into C3a and C3b. C3b binds to the pathogen leading to progressive amplification. C3b at high density are ligands for complement receptors on neutrophils and macrophages, leading to phagacytosis.-C3b binding to C3b,Bb leads to C3b2Bb (C5 convertase of alternative pathway). C5 cconvertase activates C5-C9, making a pore in the cell and killing it.-Stopping complement: DAF, CR1, MCP, CD59 and factor H.-C3a and C5a are chemotaxins and anaphylatoxins.

3. Understand clinical significance of TH1/TH2 balance.In TB there needs to be a good balance of both TH1 and TH2 cell defense.

TH1 TH2IFN-γ, IFN-α and IL2 DTHMacrophage activation Poor macrophage activation, tissue necrosisGood cell mediated immune (CMI) Active disease with poor prognosis if not tx

4. Passive Vaccination: short term tx with immunoglobulins (HNI, IVIG, etc) Used when traveling to a place of disease w/o much notice, therefore no time to get active immunity. Also used for pts with a-gammaglobulinemia where they need continual tx with HNI to provide a passive immunity for protection. Breast milk, and the Hep B immunoglobulin for the newborn are both examples of passive immunization.

Active Vaccination: receiving an actual vaccine that is long lasting. (the type we all get for school and life in general, unless you buy into the idea that it is best not to take protective measures and just rely on the herd.)

5. Attenuated Viruses: Live attenuated vaccines are usually derived from the naturally occurring germ. They can infect people, but not cause serious disease. Live attenuated vaccines are made by passing the virus through cell cultures over time until its disease-causing ability has deteriorated. Usually better because it can 1) can replicate, 2) gives both a humoral and CMI response, therefore it is usually more effective. It can also effectively immunize others by feces of the immunized person. (Sabien)

Live attenuated vaccines include:

Measles vaccine

Mumps vaccine

Rubella vaccine

Oral polio vaccine (OPV)

Varicella (chicken pox) vaccine

Inactivated Viruses: Inactivated (killed) vaccines cannot cause an infection, but still stimulate antibody production. Viruses are inactivated with chemicals such as formaldehyde. The inactivated polio vaccine (IPV) is made this way. (Salk) Inactivated viruses are used when the person is immune compromised and could react badly to the attenuated virus. Dead virus is presented on MHC class II molecules thus you get activated TH2 T cells and thus only humoral immunity.

6. Chimeric Ig:

HNI: human normal immunoglobulin

ISG: immune serum globulin

Multivalent vaccine: where you can put may be two or three different proteins instead of putting the whole organism, just use a few or combine this with different organisms for a vaccine

Recombinant vector vaccines: where an actual infectious virus is used as the vector for transmitting another pathogen. So it is like a host for putting in other pathogens. The very first recombinant vaccine that was given is the hepatitis B surface antigen.

DNA vaccines: In some cases we do not want to inject the whole virus or bacteria, we just want a certain gene with particular DNA sequence. This DNA vaccine generates both cell-mediated and humoral immune responses.

Anti-idiotype vaccines: A method to shut-off an immune response. Antibody ot antibody response.

Immune Regulation

Central Tolerance – tolerance to self based upon clonal deletion of T cells in thymus or of B cells in bone marrow.

Peripheral Tolerance- tolerance to self based upon lack of secondary signaling resulting in anergy. Example: CD28 does not meet B7 = no proliferation.

TH1 cells – produce mainly and IL-2TH2 cells – produce mainly IL-4 and IL-5

IL-3 stimulates hematopoeisis

IL-8 - chemotactic agent for neutrophils

IL-1, IL-6, and TNF-α all take part in inflammatory response

Cytokines:IL-1: made by macrophages, stimulates production of acute phase proteins by liver (C Protein and mannose binding protein) and causes fever.IL-2: necessary for T-cell response, auto stimulates T-cells and causes proliferationIL-3: Stimulates hematopoietic cells to divide.

IL-4: Made by TH2 cells – initiates proliferation and clonal expansion of B cells AND causes T cells to differentiate to TH2 variety.IL-6: Made by macrophages – makes acute phase proteins, promotes TH2 differentiation

Which will lead to B cell activation.IL-8: Made by macrophages – chemotactic agent for neutrophilsIL-10: Made by TH2 cells to inhibit TH1 differentiation – increases humeral and decreases cell mediated response.IL-12: Made by macrophages, stimulates NK cells to produce INF-γ, which further Activates macrophages, thus promoting TH1 and inhibiting TH2 differentiationIL-13: made by TH2 cells – inhibits macrophagesINF-γ: made by NK cells, CD8, and TH1 cells – activates macrophages, inhibits viral Replication, and increases MHC-1 presentationIFN-α: made by leukocytes IFN-β: made by mast cells – both do 3 things: 1)activate NK cells 2)activate anti-viral DNA enzymes 3)and increase MHC-1 presentationTGF-β: made by TH2 cells – inhibits macrophages, activates B cells, initiates isotype SwitchingTNF-α: made by macrophages – induces fever, and increases vascular permeability

Inhibitory receptors: CTLA-4 – T cellsCD 32 – B cellsKIR – NK cellsCD25 – Supressor T cells – this stimulates to make TGF-β

Septic Shock: Gram (-) infection in blood leads to systemic release o TNF- α – results in vascular dilation that leads to clotting in capillaries and reduced blood volume

Toxic Shock syndrome: TSST-1 (a superantigen) causes overproduction of CD4 cytokines (nonspecific) – leading to systemic toxicity and an impaired adaptive immunity .

Hypersensitivity

1) Major characteristics of the four types of hypersensitivity, mediators of the associated toxicity, and examples of each.

*Everything we need should be in the handout.

Type I – IgE mediator Mast cells Eiosinophils

Type II (think ceII) Hemolytic anemia (Rh+, antibiotic induced)o Cellular modifications

Type III (think III Reich SS) Serum Sickness, SLE (sys. Lupus), Arthus Reaction (Rheumatoid Arthritis)o Immune Complexes

Type IV (think poison IV) DTH, *TB test, contact dermatitis(p19s1, 2)

o T cell Mediated

2) Mediators released during Mast cell division

Tryptase Remodels CT of matrix

Histamine Toxic to parasites Permeability (endothelium) (Tight J.) SM contraction (smooth muscle)

*Anti-histamin binds H-1 receptor of endothelium and SM*Epinephrine re-establishes tight junctions and relaxes SM

IL-4 Th2 response Also required for IgE isotype switching Secondary response (IE synthesized after activation)

IL-3, IL-5, GM-CSF Eosinophils

TNF Adhesion molecule expression on epithelium Lymphocyte invasion (212-214 fig 8.11) Main initial source of TNF in inflammatory response Mediated by most cells

Leukotrienes Synthesized as secondary response mediators Powerful constrictor (Bronchiola) SM contraction Major mediator of secondary response

3) H-1 histamine receptors Both the endothelial and smooth muscle cells of blood vessels have H-1 receptor Smooth muscle contract

*In GI - Peristaltic contractions cramps*In Respiratory system - Bronchial constriction asthma

Endothelium loose junctions*In GI - Permeability Diarrhea*In Respiratory system - Secretion of mucous

4) PAF, IL-8, Leukotrienes, Tryptase

PAF = Platelet Activating Factor Released by several cell types (10.5) Platelet aggregation and degranulation Main purpose is to contain the infection & call in emergency troops

o Platelets clot & clump everything upo Chemotactic leukocytes, neutrophils, eosinophilso Activated platelets coagulation

Release mediators inflammation*TNF PAF secretion from endothelial cells

Sepsis systemic TNF PAF widespread blood clotting exhaust sup clotting factor

IL-8 Chemokine – attract neutrophils Released by MØ (pg 216 fig 8.10, 8.13) Induce endothelial adhesion by lymphocytes and netro

Leukotrienes Secondary response produced by mast cells upon activation Delated – hours later Inflammation

Tryptase Collagen remodeling Facilitates WBC traffic

5) RAST, Skin test, hyposensitization

RAST – a test to determine hypersensitivity (p. 12 s. 1) Antigen specific disks Ig Binds Ag. Radiolabeled Anti IgE Ig visualizes presence of Immunospecific IgE

Skin Test Injection of antigen to test for hypersensitivity Local injection, subcutaneous’ Wheal & flare

Hyposensitization = desensitization = allergen immunotherapy Expose someone to increasing amounts of the allergen in the hopes of desensitizing Mast Cells

to the allergen or exhausting the Mast Cells of their vasoactive components (Glossary G6) Desensitization- shifts balance between Th2 and Th1 response changing Ig production.

o IgEIgG

Autoimmune Diseases

Criteria of Autoimmune disease (p.7 s.3)1. Histopathologic evidence of immunological involvement

Damage is mediated by immune system2. Genetic factors associated with disorder (MHC)3. Self reactive Ab or T cell found. (Fig 11.24)4. Reproducable in animal model (11.24)5. Reproducable in human transfer of Ab/T cell

Autoimmune Hemolytic Anemia (p.20 s.3) (fig 11.1) Corresponds with Type II hypersensitivity Autoantibody mediated Natural – Rh factor rejection. Drug-induced – penicillin covalent modification of surface RBC protein

1. Phagocytosis – opsonization with or without compliment2. Cell lysis – MAC compliment fixation

Myasthenia Gravis (p.18 s.3) (p. 310 fig 11.14) Impaired signaling from nerve to muscle paralysis Auto-antibodies are directed toward Ach Receptor

1. Ab blocks receptor antagonist2. Ab binding endocytosis of receptor ↓ # AchR

Treatment – cholinesterase inhibitor = pyridostigmine

HLA – DR3 – associated Type II hypersensitivity

Graves Disease (p.20 s.1) (fig 11.5) Auto-antibodies agonist TSH receptor mimic TSH T4 / T3 secretion hyperthyroidism HLA DR3 Can be passed to infant from mother (IgG) Type II hypersensitivity

Systemic Lupus Erythematosis (SLE) (p.26 s.3) (p.27 s.1) Similar to Type III hypersensitivity reaction though complex 80% of individuals with compliment deficiency (C1, C4 or C2) get SLE. ↓ Compliment Immune complexes Overwhelms clearance mechanism (no ADCC

Deposition of immune complexes in tissues (kidney, skin) chronic inflammation and cell-mediated destruction.

Skin rash, blistering, photosensitivity, kidney failure, arthritis, edema, and miscarriages.Multiple Sclerosis (MS): (p.22s1-2)

T cell mediated invasion of CSF causes destruction of myelin within the CNS resulting in progressive nerve damage.

Auto-immunity toward myelin protein. Th1 CD4 mediated (type IV) activation of MØ via IFN- (pg 309) HLA-DR2 associated 3:1 Women predominance Onset 20-30’s

Hashimoto’s Thyroiditis: (p21s2-3) (fig 11.25) (p 304, 319) Cell mediated & humeral destruction of Thyroid gland ↓T4/T3 HLA-DR5 Lymphocyte infiltration of thyroid destruction lymphoidal tissue in thyroid established Auto-antigen directed toward thyroid components. IFN- expression of MHC II autoimmunity (fig 11.25)

Insulin Dependent Type I Diabetes Mellitus: (p23s1) (p 306) T cell mediated destruction of Pancreatic Islets. ↓ insulin hyperglycemia T cell mediated (type IV) CD 8 CTL HLA-DR 3, HLA-DR4 associated polymorphisms\ HLA-DR2never Gets DM

Rheumatic Fever: (p11s2) (p 323) Cross-reactive antibodies from pathogen react with self-antigens of the heart valve damage

often resulting. The antigen is similar though not identical to the antigen of the bacterial cell wall. Molecular mimicry resemblance of pathogen and host antigen. Autoimmunity is secondary to infection. Damage to heart tissue.

Rheumatoid Arthritis: (p24s3-25s1-3) (p 323) Chronic episodic inflammation of the joints due to deposition of immune complexes in the

synovium. Rheumatoid Factors (p13s1)

o B-cells produce IgM, IgG, or IgA specific for IgG Fc region. Type III Arthus reaction

o Compliment fixation increased inflammation/ WBC infiltration tissue destruction. (p25s3)

Therapy anti-TNF

HLA most associated w/ Auto-immunity HLA-DR3

HLA disease colorized on Dr. T’s slides: (p8s2) (fig 11.17) Alkylosing Spondylitis- inflammation of joints Relative risk = 87.4 Due to Cross over events

Immunodeficiency

Second slide in the handout. Slide he said would make a good question

- B-cell deficiency- susceptibility to bacterial infection- T-cell deficiency- susceptibility to fungal, protozoan and viral infections- Combined (B & T cell)- SCID diseases- Phagocytic deficiencies- chronic pyogenic bacterial infections- complement- current bacterial infections and autoimmune disease

Primary vs Secondary immune disorders

Primary- immune deficiency is the cause of disease. May be inherited or acquired.Secondary- immunodeficiencies resulting from another disease or condition. Ex.

Immunosuppression after cancer therapy or transplant, HIV, malnutrition, or leukemia/lymphoma

Primary B-cell immunodeficiency disorders

-X-linked Infantile Agammaglobulinemia (Burton’s)- Results from a defect in a tyrosine kinase (btk). Btk necessary for maturation of pre-B-cell to immature B-cell. Btk activation important for light chain rearrangement. This is almost exclusively found in males. Patient may be susceptible to viral infection, especially enteroviruses due to lack of IgA production. IVIg treatment is given. Difficult to manage with antibiotic because frequent infection still damages the tissue.

-Common Variable Hypogammaglobulinemia- Similar to Burton’s but a result of a “spectrum” of B-cell maturation defects. Besides recurrent bacterial infection the patient is susceptible to autoimmune disease. This has variable onset.

-Transient Hypogammaglobulinemia- Delayed CD4 maturation. Normal B-cells. As with most of these will not be seen for several months after birth due to the presence of mothers IgG. Will recover in 1-2 years. IVIg is rarely used.

-Selective immunoglobulin deficiencies- CH gene defect or cytokine deficiencies prevent normal isotype switching. IgA deficiency most common. Recurrent infection in airways and gut.

Antibiotic prophylaxis. IVIg treatment is dangerous. May have antibodies to foreign Ig

T-Lymphocyte disorders

- Congenital Thymic Aplasia (DiGeorge’s syndrome)- Failure of 3rd/4th pharyngeal pouches to develop causes thymic aplasia and hypoparathyroidism. Will have hypocalcemia, seizures, T-cell deficiency infections. B-cell and IgG levels normal. Treatment consists of antibiotics, fetal thymus transplantation or BM transplant. No immunizations with live attenuated vaccines.

- Chronic Mucocutaneous Candidiasis- Unknown deficit in T-cell function leads to ineffective response to candida spp. Part of APECED disease group involving a genetic disorder that is most likely autosomal recessive, associated with adrenal and parathyroid deficiencies, and B cell proliferation and malignant tumors.

- X-linked Lymphoproliferative Syndrome (Duncan’s Syndrome)- Abnormal response to EBV causes B cell proliferation and/or malignant lymphoma

Combined B and T Cell Deficiencies

- Severe Combined Immunodeficiency Disease (SCID) - Genetic defects results in absence of T and B cell precursors

- X-linked (Swiss agammaglobulinemia)- Defect in the γ-chain of many cytokine receptors (IL-2, IL-4, IL-7, IL-9, IL-15). γ-chain important in signal transduction. JAK3 is kinase associated with γ-chain and defect in JAK3 shows similar symptoms.

- Autosomal recessive forms-Adenosine deaminase (ADA)- Defect in purine metabolism. Build up of nucleotides that is toxic to T-cell. First attempt at somatic gene therapy-Purine Nucleotide Phosphorylase (PNP)- Nucleotide metabolism enzyme. Same affect as ADA.

-Symptoms and treatment- Severe infections by 1-2 years of age. Never immunize with live attenuated virus, antibiotic/IVIg doesn’t work well, bone marrow transplant and somatic gene therapy only options.

-Bare Lymphocyte Syndrome- absence of MHC I and MHC II on APC’s. Defect in transcriptional regulator proteins (CIITA and/or RFX).

-Wiscott-Aldrich Syndrome- X-linked disorder caused by a mutation in the WAS gene which incodes a protein important in the cytoskeletal rearrangement necessary before T-cells can secrete cytokines and signal B-cells. Also involves platelets. Patient will have thrombocytopenia, eczema, recurrent infections, and a high predisposition to lymphoreticular cancer. Marrow transplants are a treatment for this.

-Ataxia Telangiectasia- Mutation in gene encoding DNA repair/processing. Patients show neurological disorders including cerebellar ataxia and choreoathetosis. The disease involves thymic aplasia and low IgG. These patients have a predisposition for leukemia (T-cell) and lymphoma (B-cell).

Phagocyte Disorders

- Chronic Granulomatous Disease (CDG)- X-linked or autosomal recessive disease leading to a deficient production of hydrogen peroxides and superoxide radicals by phagocytes. Defects in one of 4 components in the NADPH oxidase system leads to this. Leads to decreased intracellular killing of bacteria and granulomas (from decreased microbicidal activity). Treat with antimicrobials and IFN-γ.- Chediak Higashi Disorder- Autosomal recessive disorder that prevents fusion of engulfed bacteria with lysosomes and prevents breakdown of bacteria. Causes partial albinism, neutropenia susceptibility to infection, peroxidase inclusions in WBC’s. Bone marrow transplant is used as a treatment.

- Leukocyte Adhesion Deficiency I (LAD I)- A genetic defect in the gene encoding the β-subunit of leukocyte integrins CR2, CR4, and LFA-1 prevents adhesion and extravasation of leukocytes. Results in recurrent bacterial infections and ineffective inflammation. Patient will have high WBC and defective would healing (umbilical cord comes off late).

Complement Deficiencies

Complement disorders are characterized by increased susceptibility to bacterial infections and are often not recognized. Early complement components (C2, C1, and C4) deficiencies are associated with autoimmune disease because early complement components help breakdown immune complexes. Immune complexes damage tissue and activate macrophages. CR1 binds C3b and C4b on red blood cells to help clear immune complexes.

- C3 deficiency is associated with recurrent bacterial infection and occurs with glomerulonephritis. C5-C9 form the membrane attack complex which is necessary for defense against Neisseria.

- Mannose Binding Lectin- Synthesized in Liver, 35% of the population has polymorphisms which are associated with decreased oligomerization and complement activation. Variants lead to increased susceptibility to HIV acquisition/progression, chronic Hep B, SLE, and autoimmune complications of CGD and protection from TB and some forms of meningitis.

Acquired Immunodeficiencies

- HIV- Retroviral pathogen. RNA virus (negative strand). Replicates using RT which has a high error rate. Attaches to CD4 via gp120 or CCR5. Loss of T-Helper population and T-helper function. Increased incidence of opportunistic infection and malignancy.

Transplatations

DefinitionsAutograph: donor is the recipient.Isograph: donor and recipient are the same species and have the same genetic make-up

(identical twins).Allograph: donor and recipient are the same species but have a different genetic make-up.Xenograph: donor and recipient are different species.

Limitations1. supply – there are not enough cadaveric or living donors to keep up with the potential

recipients.2. rejection – due to imperfect immunosuppressive agents.3. increased risk of infection and malignancy.

Allograft Rejections 1. hyperacute graft rejection

Similar to blood transfusion reaction – A antigen and B antigen that determine blood type are also found on endothelial surfaces of blood vessels.

Scenario – If you put an organ from a donor with A blood (A antigen on vessels of organ) into a person with B blood (blood that contains anti-A antibodies), the anti-A antibodies of the recipient will attack the A antigens on the vessels of the donated organ.

Result – a) activation of the clotting cascade leading to microvascular occlusion – the organ clots off and turns blue almost immediately. b) complement and PMN destroy endothelium – histologically you will see a torn apart endothelium, fibrinoid necrosis, and considerable hemorrhage.

2. acute graft rejection Cell mediated allograph reaction due to difference in HLA type (mainly). Kinetics is similar to a primary immune response to an invading pathogen (1-2

weeks). If the recipient already has anti-HLA antibodies to the donor organ (multiparous women, individuals with multiple blood transfusions, or individuals already having received a transplant), the kinetics is similar to a secondary immune response (>1 week).

Two forms: cellular and vascular (humoral), the cell mediated form being the most common.

Cell mediated 1. direct allorecognition: See figure 12.16, pg 344. Donor antigen-presenting

cells from the graft migrate to the secondary lymphoid organs of the recipient where the recipients Tcells are activated sufficiently by the donor ‘self’-HLA complexes. A recipient Tcell response is then mounted against the donor organ.

2. indirect allorecognition: Recipient antigen presenting cells endocytose particles of damaged donor tissue and present donor HLA epitopes to the

recipient Tcells. Recipient Tcell mount a response against the donor organ (specifically against the donor HLA).

3. chronic graft rejection Occurs within months following transplantation. Apparently due to both cell-mediated and antibody mediated immunity – slow

infiltration of immune cells. Usually involves narrowing of vasculature and thickening of basement

membranes – histologically find proliferative inflammatory lesions of small arteries.

4. graft vs. host rejection (Graft vs Host Disease – GVHD) Almost exclusive to BMT (but can happen with liver). Immune cells of the graft attack the recipient – particularly important with BMT

because you have essentially replaced that immune system of the recipient with that of the donor so the donated immune system recognizes the recipient as “foreign”. HLA matching becomes extremely important.

Two to three weeks post transplant.

Lab Tests for Donor/Recipient Selection1. ABO match – to avoid hyperacute graft rejection2. PRA (Panel reactive Antibody)

assay used to assess if the potential recipient already has preformed antibodies against HLA types.

recipients serum is mixed with a panel of several tissue types to determine which HLA types the recipient already has antibodies against.

Reported as a percentage – the higher the percentage, the more preformed antibodies a person already has, the more difficult it is to find a match.

3. MLC (Mixed Leukocyte Culture) In-vitro correlate to graft rejection Leukocytes from the recipient are cultured with irradiated lymphocytes of the

donor (which cannot proliferate but can excite the recipient cells). In 3-4 days time the recipient lymphocytes will have proliferated if they are reactive to HLA on the donor lymphocytes.

Especially valuable for determining HLA-D__ compatibility (MHC class II) When appropriate –

4. DNA typing5. Serological

Antibodies to known HLA antigens (I think this is the PRA above) Compliment cell mediated cytotoxicity Detects mainly HLA-A,B,C (MHC class I) and some HLA-DR, DQ

Opportunistic Neoplasms1. See Tumor immunology lecture. (Below)2. include: Kaposi Sarcoma, non-Hodkins Lymphoma, Melanoma

Allograft Management

1. better match = better survival2. shorter cold ischemia = better survival3. Mainstay of treatment

Prednisone Calcineuron Phosphatase Inhibitor Rapamycin

4. other available solutions anti-metabolites – not used much because of toxicity

depletional agents – anti lymphocyte serum

Tumor Immunology

1) Tumor-specific antigens (TSA) are antigens that are characteristic of tumor cells and are not expressed by normal cells.

Tumor-associated antigens (TAA) are antigens characteristic of certain tumor cells that are also present on some types of normal cells.

2) Carcinoembryonic antigen (CEA) is a large glycoprotein of epithelial cells which has increased expression on dividing cells. It was one of the first cell-surface molecules designated as a tumor antigen. Initially shown to be expressed by cells of human colon cancer and by fetal gut cells, thus the name.

3) Anti-HER2 Ab (Herceptin) is a monoclonal antibody against epidermal growth factor receptor-2 (HER2). HER2 is overexpressed in about 30% of breast cancers. Herceptin has shown promising data in metastatic breast cancer. Some cardiac toxicity. Herceptin plus chemotherapy is more beneficial.

Anti-CD20 (Rituximab) is a humanized monoclonal antibody to CD20 used in the treatment for non-Hodgkins lymphoma. Uses the following mechanisms of action: ADCC, complement dependent cytoxicity, and direct effects of CD20 ligation (which are inhibition of proliferation, induction of apoptosis, and sensitization to chemotherapy).

4) M-protein (Myeloma protein) is the homogenous intact human antibody used to help determine immunoglobulin structure and whose presence in a single patient allowed the identification of the IgD class.

Bence Jones Proteins are dimmers of immunoglobulin light chains in the urine of patients with multiple myeloma.

PSA (prostate-specific antigen) is widely used for screening and early detection of prostate cancer.

5) LAK and TIL cell therapy LAK (lymphokine activated killer cells)-The patient’s blood lymphocytes are expanded with IL-2 and returned together with more IL-2.TIL (tumor infiltrating lymphocytes)

-The lymphocytes infiltrating the patient’s tumor are isolated, expanded in vitro with cytokines and re-administered to the patient.

6) Tumor “Escape” Mechanisms Tumor cells secrete immunosuppressive cytokines (eg. TGF-beta or IL-10) Tumors may express Fas ligand which induces cell death in T cells which express Fas

(death receptor) Evolution of tumor variants that no longer express tumor antigen Many tumor antigens are self antigens and poorly recognized by T cells Loss of expression of MHC Class I (so, escape from cytotoxic T cells Lack of costimulatory molecules on Tumor cells results in failure to stimulate T cells

which become anergic.

7) The Epstein-Barr Virus (EBV) is associated with Burkitt’s lymphoma (cancer of B lymphocytes), Nasopharyngeal carcinoma, and B-cell lymphoproliferative disease. Areas of high incidence include West Africa, Papua New Guinea, Southern China, Greenland (Inuit) and immunosuppressed or immunodeficient patients.