Ch 16 Immune

Manipulation of the Immune Response

Overview

This chapter explores how the immune response can be manipulated for therapeutic purposes, focusing on immunosuppression, immunological cancer treatments, and vaccines. These strategies are central to modern medicine, especially in the treatment of autoimmune diseases, cancer, and prevention of infectious diseases.

Immunosuppression

Cytotoxic Drugs

Cytotoxic drugs are agents that kill dividing cells, including hematopoietic stem cells (HSCs), and are used to suppress the immune system.

• Inhibitors of Nucleotide Synthesis: Drugs such as azathioprine and mycophenolate block the synthesis of nucleotides, preventing cell division.

• DNA Damage: Cyclophosphamide is a chemotherapy drug that damages DNA, leading to cell death.

• Applications: High doses are used to destroy bone marrow in preparation for bone marrow transplantation (BMT).

• Side Effects: These drugs also damage other rapidly dividing tissues, such as skin, gut lining, and non-immune tissues derived from bone marrow.

Mechanism of Action of Corticosteroids

• Intracellular Receptor Activation: Corticosteroids bind to intracellular receptors, activating transcription of many genes.

• Inhibition of NFκB: They inhibit the transcription factor NFκB, thereby reducing inflammation.

• Side Effects: Many side effects are associated with corticosteroid use due to their broad impact on gene expression.

T-cell Inhibitors

• Examples: Cyclosporin A, Tacrolimus, Rapamycin

• Mechanism: These drugs interfere with T cell signaling, reducing the expression of cytokines such as IL-2, which is necessary for T cell proliferation.

• Result: Reduced T cell population leads to decreased B-cell and macrophage activity.

Antibody-Based Immune Modulation

Using Antibodies as Drugs

• Types: Polyclonal and monoclonal antibodies can be used to kill or block the activity of specific cells or molecules.

Types of Monoclonal Antibodies

• Fully Mouse (-omab): Can provoke immune reactions in humans.

• Chimeric (-ximab): Part mouse, part human.

• Humanized (-zumab): Mostly human, with small mouse components.

• Fully Human (-umab): Least likely to provoke immune reactions.

Humanized Mouse Antibodies

• Genetic Engineering: Human antibody genes are inserted into mice, producing antibodies that do not provoke immune responses in humans.

• Applications: Antibodies to human proteins (e.g., anti-TNF-α) can be made in mice for therapeutic use.

Monoclonal Antibodies Developed for Immunotherapy

Monoclonal antibodies are designed to target specific molecules or cells involved in disease processes. Below are examples of monoclonal antibodies and their uses:

Generic Name	Specificity	Mechanism of Action	Approved Indication
Rituximab	Anti-CD20	Eliminates B cells	Non-Hodgkin's lymphoma
Alemtuzumab	Anti-CD52	Eliminates lymphocytes	Chronic myeloid leukemia
Muromonab (OKT3)	Anti-CD3	Inhibits T-cell activation	Kidney transplantation
Infliximab	Anti-TNF	Inhibits inflammation induced by TNF-α	Crohn's disease
Adalimumab	Anti-TNF	Inhibits inflammation induced by TNF-α	Rheumatoid arthritis
Tocilizumab	Anti-IL6R	Blocks inflammation induced by IL-6 signaling	Muckle-Wells syndrome
Canakinumab	Anti-IL1β	Blocks inflammation induced by IL-1	Muckle-Wells syndrome

Current Monoclonal Antibody Drugs and Applications

• Drugs: Examples include Repatha (evolocumab), Humira (adalimumab), Rituxan (rituximab), Opdivo (nivolumab), and many more.

• Applications: Cancer, rheumatoid arthritis, multiple sclerosis, cardiovascular disease, Crohn's disease, ulcerative colitis, psoriasis, eosinophilic asthma, hyperlipidemia/atherosclerosis, transplant rejection, and other conditions.

Mechanism Example: Repatha (Evolocumab)

• Function: Lowers cholesterol by reducing recycling of the LDL receptor (LDL-R) by hepatocytes.

• Mechanism: Evolocumab binds to PCSK9, preventing LDL-R degradation and increasing clearance of LDL cholesterol.

Antibody Therapy for Autoimmune Diseases

• Anti-TNF-α Antibodies: Used to treat rheumatoid arthritis (RA) by reducing pain, joint swelling, and inflammation markers.

• Anti-IL-1 and Anti-IL-6 Antibodies: Can help in other autoimmune diseases.

Antibody Therapy for Multiple Sclerosis (MS)

• Anti-Integrin Antibodies: Prevent adhesion of immune cells to brain epithelium, reducing new brain lesions.

Rituximab for Autoimmunity

• Target: CD20 on B cells.

• Effect: Causes elimination of B cells via multiple pathways, including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity, and phagocytosis.

Bispecific Antibodies

• Definition: Recombinant antibodies engineered to bind two different antigens.

• Application: Can link immune cells to tumors, enhancing immune-mediated tumor cell killing.

Induction of Tolerance

Methods of Inducing Tolerance

• Allergy Shots: Gradual exposure to allergens to induce immune tolerance.

• Oral Tolerance: Feeding antigens to induce tolerance (effective in animal models).

• Gene Therapy: Injecting DNA encoding antigens to present them as 'self' and induce peripheral tolerance.

• Manipulation of TH1 vs TH2 Responses: Switching immune response types (e.g., antibody to IL-4 switches to TH1 response, clearing intracellular bacteria).

Immunological Cancer Treatments

Immune Therapies for Cancer

• Natural Immunity: The immune system can recognize and fight cancer cells.

• Therapeutic Modulation: Immune manipulation is often used alongside other cancer therapies.

Early Cancer Experiments

• Immunological Memory: Injection of irradiated (non-growing) cancer cells can induce immune memory against specific tumor antigens.

Tumor Antigens

• Mutation of Self Proteins: New peptides may be presented and bind self-MHCs.

• Gene Activation: Genes not normally expressed in adult cells may be turned on.

• Overexpression: Normal proteins may be overexpressed.

• Viral Proteins: Proteins from cancer-causing viruses may be expressed.

Immune Surveillance

• Escape Mechanisms: Tumors that form have escaped immune killing; immunosuppression increases cancer risk in transplant patients.

How Cancer Cells Avoid Immune System

Mechanism	Description
Low Immunogenicity	No peptide/MHC ligand, no adhesion molecules
Tumor Treated as Self	Tumor antigens taken up and presented as self
Antigenic Modulation	Antibody against tumor antigen induces antigen loss
Tumor-Induced Immune Suppression	Factors such as TGF-β, IL-10, and regulatory T cells suppress immune response
Tumor-Induced Privileged Site	Physical barriers prevent immune cell access

MHC I Expression in Cancer Cells

• Loss of MHC I: Many cancer cells lose MHC I expression, making them less visible to cytotoxic T cells.

• NK Cell Activity: NK cells can kill cells lacking MHC I, but some cancer cells express low levels to avoid both NK and Tc cell killing.

Monoclonal Antibodies to Fight Cancer

• Direct Targeting: Antibodies can bind tumor cells and recruit immune cells (ADCC), deliver toxins, or radioactive agents to kill tumor cells.

Cancer Vaccines

• HPV Vaccine: Prevents cervical cancer by targeting HPV strains responsible for most cases (e.g., Gardasil-9).

• Therapeutic Vaccines: Mix tumor cells with adjuvants to stimulate immune response against established cancers.

Transfection of Tumors with B7

• Mechanism: Tumor cells engineered to express B7 act as antigen-presenting cells, activating CD8 T cells against the tumor.

CAR-T Cells

• Definition: CAR-T cells are T cells engineered to express chimeric antigen receptors (CARs) that target specific tumor antigens.

• Mechanism: CAR combines the antigen-binding site of an antibody with T cell receptor signaling domains, activating T cells against tumor cells.

• Engineering: CAR-T cells can be personalized to target patient-specific tumor antigens.

CAR-T Cell Therapy Process

1. Remove blood from patient to isolate T cells.

2. Insert CAR gene into T cells in the lab.

3. Grow millions of CAR-T cells.

4. Infuse CAR-T cells back into the patient to target and kill cancer cells.

CAR-T Cells: Current Status

• Personalization: Receptors are tailored to patient's tumor and immune antigens.

• Efficacy: High cure rates in refractory/secondary tumors (up to 94%).

• Side Effects: Cytokine release syndrome (shock-like) in >50% of patients.

• Cost: Extremely expensive ($400,000–500,000 plus hospitalization).

• Challenges: Tumor antigen escape; initial efforts focused on CD19 (B cell leukemias), new efforts on solid tumors.

Additional info: These notes are based on immunology and medical biotechnology, not organic chemistry. No organic chemistry mechanisms, structures, or reactions are covered in this material.