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OVERVIEW of THE IMMUNE SYSTEM

Diseases

Immunocompetence/Immunodeficiency

Infectious Disease

InflammationAllergy

Organ-Specific Immunologic Disorders

Connective Tissue Disorders

Immunohematology

Transplantation Immunology

Cancer/Therapy

Reproductive Immunology

Neuro Immunology

Historical Immunology

Infectious Disease

Serology

Immunochemistry

Cellular Immunology

Immunological Heroes – Nobel Prize WinnersMetchnikoff, Bordet, Landsteiner, Macfarlane Burnet, Porter, Dausset

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Host Defense Systems

A. Innate (Nonspecific) Immunity -

1. Skin & Mucous Membranes - First Line of Defense

a. Skin

b. Membranes

Respiratory Tract

Eyes

c. Stomach

d. Genitourinary

2. Immunological Surface Protective Mechanisms

a. Immunoglobulins A and E

IgE

IgA

3. Non-Ig Humoral Factors(Physiologic Barriers)

4. Neutrophil/Macrophage Functions - a. Phagocytosis

5. Inflammatory Response

B. Adaptive (Specific) Immunity

1. Characteristics

a. Recognition

b. Specificity

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c. Effector Response

d. Memory

e. Heterogeneous (Diversity)

2. Cells of the Immune System

a. Lymphocytes

B- Cells

T- Cells

b. Antigen Presenting Cells Macrophages & Others with MHC

3. Lymphocyte Functions

a. Humoral Response

b. Cell Mediated Response

Immune Mechanisms In Tissue Damage

Double Edge Sword

Type I Anaphylactic Type III Immune Complex

Type II Cytotoxic Type IV Delayed Hypersensitivity

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NONLYMPHOID CELLS OF THE IMMUNE SYSTEM

I. The Myeloid System

A. Granulocytic Series

1. Neutrophils

2. Eosinophils

3. Basophils

B. Platelets

C. Mast cells

II. Mononuclear-Phagocytic System

A. Monocytes

B. Macrophage

1. Structure

2.Location

3. Functions

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a. Phagocytosis

b. OtherHas surface receptorsSynthesize & secrete proteinsPromotes healing

c. Antigen Processing

d. Antigen Presentation

Th cell with interleukin 1

e. Activation - Both Tc cells and B cells

C. Dendritic Cells

1. Description -

a. Myeloid

b. Langerhans

c. Interstitial

d. Lymphoid

2. Follicular Dendritic Cells

3. Development

III. Lymphocytic System - 15-20% of peripheral WBC's

T-Cells- 70-90% B-Cells- remainderA. Function

B. Morphology

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LYMPHOID CELLS OF THE IMMUNE SYSTEM

I. The Lymphoid Cells

A. General Description

B. Morphology-

C. Stages of Development

1. Small Lymph------> Go, G1, S1, M

D. Life Span

E. Lymphocyte Surface Molecules

1. Antibodies

2. Major Histocompatibility Antigens (MHC)

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3. TCR - T receptor complex

4. CD Antigens

a. Kinds of Lymphocyte Receptors- Antigen

- Cytokine

-Antibody

-Complement

b. Lymphocyte Adherence Molecules-

II. B-Lymphocytes

A. Description

III. T- Lymphocytes

A. Description

B. Role of the Thymus

C. Mature Peripheral T-Cell Populations

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1. Naive T Cells

2. Effector Cells

a. Th

b. Tc

c. Ts

d. Tdth

3.Memory Cells

IV.Killer Cells and Natural Killer Cells

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ORGANS OF THE IMMUNE SYSTEM

I. Lymphoid System

A. Description

II. Organs of the Immune System

A. Primary

1. Thymus

a. Structure

Lobes

Cortex - Germinal Centers

Medulla

b. Function

2. Bone Marrow - Bursa of Fabricius equivalent

a. Structure

b. Function

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B. Secondary

1. Lymph Node

a. Structure

Cortex

Paracortex

Medulla

Germinal Centers

b. Function

2. Spleen

a. Structure

White Pulp

Germinal Centers

Red Pulp

b. Function

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3. Mucosal-Associated Lymphoid Tissue (MALT)

a. Structure & Location

M Cells

b. Function

III. Lymphocyte Circulation

A. Circulation Diagram

B. Circulation - Vessels

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ANTIGENS

Molecular Events

Antigens

Immunocompetent Cells

Membrane Events

Information Transfer

Nuclear Events

Cytoplasmic Events

Immune Molecules

Humoral

Cell Mediated

Definitions/Concepts

Antigens

Epitope

B-cell

T-cell

Hapten

Crossreactivity

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Heterophile

Mitogen

Antigen Classification

Chemical Basis

Complete

Incomplete

Common Antigens

Bacteria

Viruses

Blood Elements

Drugs

Organ Grafts

Autoantigens

Fetuses

Factors Influencing Immunogenicity

1. Antigen Foreigness

Graft

Xenograft

Allograft

Isograft

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Autograft

2. Antigen Complexity & Size

3. Catabolism/Degradability

4. Antigen Dose

5. Route of Immunization

6. Immunocompetence

7. Genetics

8. Nutritional Factors

Summary

1. The physical properties of the antigen2. The biological system3. The route of administration of the antigen4. The method of immunization5. The dose of the antigen

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IMMUNOGLOBULINSI. Immunoglobulins

A. General Descriptions

B. Basic Immunoglobulin Structure

1. AbbreviationsF - fragment, ususally obtained by digestionab- antibody-combining portionFc- crystallizable portionC - constant regionV - variable regionH - heavy chainL - light chain

2. Purified Molecule Visualized

3. Heavy Chain

4. Light Chain

C. Classes - 5

D. Immunoglobulin Variants - Antibody Heterogeneity

1. Isotypic variants

2. Allotypic variants

3. Idiotypic variants

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E. Basic Structure of Five Classes

1. IgG

2. IgD

3. IgE

4. IgA

5. IgM

F. Properties & Biological Activities

G . Subclasses 1.

2.

3.

H. B-cell receptors

I. The Immunoglobulin Superfamily

J. Monoclonal Antibodies

Problems

Production

Limitations

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COMPLEMENT

I. Definition:

A. Complement - An interrelated group of serum proteins that is maintained in a biologically inactive, native state and is enzymatically and sequentially activated by the combination of complement-fixing antibody with antigen or by other alternate substances. The essential feature is the sequential enzymatic cleavage of each complement component (C'1a is an exception). The system is designed to:

1. Lysis

2. Inhance phagocytosis

3. Participate in Inflammation

4. Remove immune complexes

II. Characteristics of Complement

A. Components

1. Classical

2. Alternate

3. Terminal

4. Control Proteins

B. Terminology

C. Physiochemical

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III. Classical Complement Pathway

A. Activation

B. Reaction Mechanisms

C. Steps in Reaction

IV. The Alternate Complement Pathway

A. Description

B. Activators

C. Reactions

V. Terminal Complement Pathway

A. Description

B. Reaction

VI. Regulation of the Complement System -

A. Labile

B. Inhibitors

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VII. Receptors for Complement A. Description

B. Receptors

VIII. Biological Consequences of Complement

A. Cell Lysis

B. Inflammatory Response

C. Opsonization

D Virus Neutralization

E. Removal of Immune Complexes

IX. Complement Deficiencies

A. Inborn Abnormalities

B. Acquired Abnormalities

1. Increased utilization

2. Decreased synthesis

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THE MAJOR HISTOCOMPATIBILITY COMPLEX

I. Location

A. Class I

B. Class II

C. Class III

II. Structure and Function

A. The Class I Genes and Proteins

1. Polymorphic

2. Co-dominate, allelic, inherited

3. -1, 2, 3

4. β - 2 Microglobulin

5. Function

B. The Class II Genes and Proteins

1. Two-peptide protein

2. Variation

3. Function

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ANTIGEN PRESENTATION

I. General Background

A. Self-MHC Restriction

B. APC Cells

C. Target Cells

II. Antigen Processing

A. Endogenous

B. Exogenous

1. Endocytosis

2. Phagocytosis

III. Antigen Presentation -

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T-CELL RECEPTOR (TCR) T CELL MATURATION, ACTIVATION, & DIFFERENTIATION

I. T-Cell Receptor (TCR)

A. TCR Structure

B. T-Cell Receptor Complex: TCR-CD3

C. T-Cell Accessory Membrane Molecules -

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T-Cell Maturation, Activation, and Differentiation

I. T-Cell Maturation

II. Thymic SelectionA. Selection of the TCR

1. Positive

2. Negative

III. T-Cell ActivationA. Peripheral Circulation

B. Antigen Encounter

C. Mechanism

D. Signaling Pathways

E. Co-Stimulatory Signal

F. Clonal Expansion vs. Clonal Anergy

G. Super Antigen

III. T-Cell Differentiation

A. Effector Cells

B. Memory Cells

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B-Cell Generation, Activation, & Differentiation

I. General Description

II. B-Cell MaturationA. Bone Marrow

1. Stages - Pro-B

2. Stages - Immature B

3. Selection

III. B-Cell Activation and Proliferation A. General Description

1. Site

2. Paracortex/Cortex

3. Antigen

B. Thymus-Dependent and Thymus-Independent Antigens

1. Properties

2. Thymus-Independent

3. Thymus - Dependent

C. Signaling

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IV. The Humoral Response

A. Primary

1. Description -

2. Characteristics -

B. Secondary

1. Description

2. Characteristics

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CYTOKINES

I. Cytokines

A. Function

1. Autocrine

2. Paracrine

3. Endocrine

B. Biological Activities

C. Interleukins

1. Interleukin 1

2. Interleukin 2

D. Interferons

1. α and β

2. γ

E. Tumor Necrosis Factors

1. Tumor necrosis factor - alpha

a. Trigger

b. Sequelae

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II. Secretion of Cytokines by Th

A. Th1 Subset

B. Th2 Subset

Leprosy -

III. Cytokine Receptors

A. Structures

B. Function

IV. Cytokine-Related Diseases

A. Bacterial Septic Shock

B. Bacterial Toxic Shock

C. Chagas' Disease

V. Therapeutic Uses of Cytokines

VI. Cytokines In Hematopoiesis

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LEUKOCYTE ACTIVATION AND MIGRATION

I. General

A. Lymphocyte Recirculation

B. Leukocyte Migration

C. Cell-Adhesion Molecules

1. Selectins/Mucins

2. Integrins/ICAMS - Ig Superfamily

D. Neutrophil and Lymphoycyte Extravasation - See online @ www.whfreeman.com/immunology6e

E. Lymphocyte Exravasation

1. High-Endotheial Venules

2. Homing of Lymphocytes

II. Mediators of InflammationA. Biologic Activity of Mediators

B. Types1. Chemokines

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2. Plasma Enzyme Mediators

a. Kinin System

b. Clotting System

c. Fibrinolytic System

d. Complement System

3. Lipid Inflammatory Mediators

a. Slow Reacting Substance of Anaphylaxis (Leukotriens)

b. Prostaglandins

c. Platelet Activating Factor

III. Acute Inflammatory Response

A. Causes of Inflammation

B. Hallmarks of Inflammation

C. Features of Inflammation

IV. Acute Phase (Local)

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A. Increased vascular permeability

B. Chemotaxis

C. Phagocytosis

V. Acute-Phase (Systemic) Response

A. Characteristics

1. Fever

2. Acute Phase Proteins

a. Example

C- Reactive

VI. Chronic Inflammation

A. Description

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CELL-MEDIATED CYTOTOXIC RESPONSES

I. Description

II. Effector ResponsesA. Cells involved

1. Specific Cells

2. Non-specific Cells

B. Categories of Cell Mediated Immunity

1. Direct Cytotoxic Response

2. Delayed-type Hypersensitivity Reactions

C. General Properties of Effector T-Cells

III. Cytotoxicity Involving Antigen-Specific Cytotoxic Tc

A. Antigen-specific cytoxicity

1. Description

2. Tc-Cell Generation

3. CTL-Mediated Destruction of Target Cells

4. Natural Killer Cell (NK) Mediated Destruction

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5. Antibody-Dependent Cell-Mediated Cytolysis

IV. Graft vs Host Disease

A. Description

B. Symptoms

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HYPERSENSITIVITY REACTIONS

I. Hypersensitivity

A. Definition

B. Types

1. Humoral (Immediate)

2. Cell Mediated (Delayed)

3. Gell & Coombs Classifications

II. Type I – Anaphylactic

A. Components

B. Systemic Anaphylaxis

1. Symptoms

2. Causes

3. Mechanism

4. Treatment

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C. Localized - Atopic Allergy

1. Description

2. Causes

3. Mechanisms

a. Food Allergy

b. Upper Respiratory

c. Lower Respiratory

4. Treatment

D. The Late Phase Reaction

E. Detection of Type I Hypersensitivity

III. Type II - Cytotoxic

A. Mechanism

1. Antibody Mediated Tissue Damage

2. Blockage of Normal Cell Function

3. Complement-Mediated Cell Lysis

4. Antibody Dependent Cell Mediated Cytolysis (ADCC)

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IV. Type III - Immune Complexes

A. Description

B. Localized

1. Arthus Reaction

C. Generalized

1. Serum Sickness

a. Symptoms

2. Others

V. Type IV - Cell Mediated (DTH)

A. Description

B. Primary (Sensitization Phase)

C. Secondary (Effector Phase)

D. Cytokines and Chemokines Involved

E. Protective Role of DTH

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F. Examples

1. Tb, Leprosy, Histo, Cocci

2. Contact Sensitivity

G. Detection

1. Tb, Histo, Cocci

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TOLERANCE & AUTOIMMUNITY

I. Definitions

A. Autoimmunity

B. Self-Tolerance

1. Central

2. Peripheral

3. Aptosis

II. Establishing and Maintaining Tolerance

A. Central

B. Peripheral

C. Peripheral Regulatory T-Cells

D. Sequestered Antigen

E Tolerance Failure

III. Proposed Mechanisms for Induction of Autoimmunity

A. Release of sequestered Antigen

B. Molecular Mimicry

C. Inappropriate Expression of Class II MHC Molecules

D. Polyclonal B-Cell Activation

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IV. Organ Specific Autoimmune Disease

A. Auto-Antibodies - Cell Surface Components

1. Stimulating - Grave's Disease

2. Blocking - Myasthenia Gravis

B. Direct Cell Damage - Auto-Antibodies

1. Sensitized T-cells + Auto-Antibodies Hashimoto's Thyroiditis

2. Auto-Antibodies - Goodpasture's Syndrome

V. Systemic Autoimmune Diseases

A. Auto-antibody/Antigen Complexes

1. Systemic Lupus Erythematosis

2. Rheumatoid Arthritis

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MHC AND TRANSPLANTATION IMMUNOLOGY

I. General Statements

A. Givens

1.

2.

3.

B. System Involved

C. Early Pioneers

1. Dausset2. Payne3. Terasaki

II. Major Histocompatility Complex

A. Gene

B. Locus

C. Biochemical Make-up of Transplantation Antigens

1. Class I

2. Class II

D. Alloantigenic Determinants

1. HLA SpecificitiesHLA - A, HLA - B , HLA - C

HLA - DR, HLA - DQ, HLA - DP

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E. Nomenclature

G. Immunogenetics

1. Phenotype

2. Haplotypes

3. Inheritance of HLA Antigens

III. Testing

A. Lymphocytotoxicity Testing

B. Mixed Lymphocyte Culture

C. Determining Genotypes

Example

IV. Transplantations

A. Organ and Cell Transplantations

. B. Effects of Matching

C. Mechanisms Involved in Graft Rejection

D. Clinical Manifestations of Graft Rejection

1. Antibody Mediated

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E. General Immunosuppressive Therapy

1. Mitotic Inhibitors

2. Fungal Metabolites

F. Specific Immunosuppressive Therapy

1. Antibodies

2. Signal Blocking

G. Immune Tolerance to Allographs

1. Privileged Site

2. Specific Tolerance

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IMMUNE RESPONSE TO INFECTIOUS DISEASE

I. Basic Definitions

A. Adaptive Immunity

1. Humoral

a. Actively Acquired

i. Natural

ii. Artificial

b. Passively Acquired

i. Natural

ii. Artificial

B. Innate Immunity

1. Barrier Cells

2. Phagocytic Cells

3. Mediator Cells

4. Acute Phase Response

5. Inflammation

6. Phagocytosis

II. Process of Phagocytosis A. Steps

1. Chemotaxis and Attachment

2. Ingestion

3. Killing

a. Non-Oxidative

b. Oxidative

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4. Digestion and Release

III. Immunity to Infectious Pathogens

A. Bacterial

1. Nonspecific

2. Specific vs Evasion Mechanisms

a. Attachment to host cells

b. Proliferation

c. Invasion of Host Tissue

d. Toxin Induced Damage to Host Cells

B. Viral

1. Nonspecific

2. Specific

3. Evasion

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C. Protozoa

1. Nonspecific

a. Species and genetic influences

2. Specific

3. Evasion

D. Helminths

1. Nonspecific

a. competition

2. Specific

a. IgE

E. Fungal Diseases

1. Innate

2. Acquired

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AIDS AND OTHER IMMUNODEFICIENCIES

I. General

A. Cells

1.

2.

3.

B. Derivation of Immunodeficiencies

1. Primary Immunodeficiency

2. Secondary - May be acquired

C. Distribution -

1. Phagocytic - 14%2. Humoral - 53%3. Cell-Mediated - 7%4. Combined - 23%5. Complement & Undeciphered - <3

II. PrimaryA. Phagocytic Cell Deficiencies

1. Cause

2. Diagnosis

3. Diseases

a. Reduction in Function

1.1 Chronic Granulomatous Disease

1.2 Chediak-Higashi

1.3 Bare Lymphocyte Syndrome

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b Reduction in Neutrophil Count

B. Humoral - Immunodeficiencies Involving B Lymphocytes

1. Diagnosis

2. Diseases

a. Bruton's Agammaglobulinemia

b. Common Variable Hypogammaglobulinemia

c. Hyper IgE - Job's Disease

d. Selective IgA Deficiency

C. T-Cell-Mediated Deficiencies

1. Diseases

a. DiGeorge's Syndrome

D. Combined B-Cell and T-Cell Immunodeficiencies

1. Diseases

a. SCID

b. Wiskott-Aldrich Syndrome

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c. Bare-lymphocyte Syndrome

E. Treatment

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III. Secondary Immunodeficiencies - AIDS

A. Epidemiology

B. Etiologic Agent

C. Transmission

D. Regulatory Genes

E. Laboratory Tests

1. Hematology

2. Serology

3. Antigen Tests

F. Pathogenesis

1. T-cells

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2. T-helper

3. B- Cells

G. Clinical Diagnosis

H. Treatment

I. Vaccines

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CANCER AND THE IMMUNE SYSTEM

I. General Information

A. Description & Terms

1. Benign

2. Malignant

3. Cancer

4. Metastasis

5. Embryonic origin

a. Carcinoma

b. Sarcoma

c. Leukemia & lymphoma

B. Properties of Cancer

1. Clonally Derived

2. Change in Cell Growth

3. Altered Tissue

4. Biochemical Changes

5. Disorganized Cytoskeleton

6. Chromosomal Abnormalities

II. Etiology

A. Chemical

B. X-Ray

C. Viruses

D. Human Oncogenes

III. Tumor Antigens

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A. General

1. TATAs - Tumor Associated Transplantation Antigens ( Inappropriate expression of embryonic gene)

a. Oncofetal Antigens

CEA

AFP

2. TSTAs - Tumor Specific Transplantation Antigens (Mutation generates new peptide in Class I MHC molecules)

a. Chemical or Physical

b. Virally induced

3. TATAS - Oncogene Proteins as Tumor Antigens - (Over expression of normal proteins).

IV. Tumor Immunity

A. General

B. Tc cells

C. NK cells

D. Macrophage

V. Tumor Evasion of the Immune System

A. Reduction In Class I MHC Molecules

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B. Modulation of Tumor Antigens

C. Immune Enhancement

D. Lack of Co-Stimulatory Signals

E. Immunodeficiency

VI. Cancer Therapy - Surgery - Radiotherapy-Chemotherapy - ImmunotherapyA. Surgery

B. Immunotherapy

1. Defined

2. Manipulation of Co-Stimulatory Signals

3. Monoclonal Antibodies

4. Enhancement of APC Activity

5. Cytokine Therapy

3/09

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