Week 7 Immunology: Tumor Immunology, Solid Organ Transplantation and Bone - PowerPoint Presentation

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Week 7 Immunology: Tumor Immunology, Solid Organ Transplantation and Bone Marrow Transplantation

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Chapter 33

Tumor Immunology

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Figure 33-01.

   Embryonic primary germ layers.

(Redrawn from Larsen WJ:

Human embryology,

ed 3, Philadelphia, 2001, Churchill Livingstone.)

Slide4

Introduction

Oncology: study of neoplasms: benign or malignant

Benign Tumors:

encapsulated,

slow growing,

non-spreading

Low mitotic activity

Resembling parent tissue

Malignant Tumors

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Malignant Tumors: carcinoma (glandular.-adenocarcinoma); squamous origin: squamous cell carcinoma

Increase in the number of cells that accumulate

Easily invades other tissues

Show nuclear and cytoplasmic characteristics

Adhesion molecules

Secretion of transforming growth factor alpha: promotes angiogenesis

recurrence

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Figure 33-02.

   

Stem cell systems.

Normal tissues arise from a central stem cell that grows and differentiates to create progenitor and mature cell populations. Key properties of normal stem cells are the ability to self-renew (indicated by

curved arrow

), multilineage potential, and extensive proliferative capacity. Cancer stem cells arise by means of mutation in normal stem cells or progenitor cells and subsequently grow and differentiate to create primary tumors (

broken arrow

indicates that specific types of progenitors involved in the generation of cancer stem cells are unclear). As with normal stem cells, cancer stem cells can self-renew, give rise to heterogeneous populations of daughter cells, and proliferate extensively.

(Redrawn from Jordan CT, Guzman ML, Noble M:

N Engl J Med

355(12):1255, 2006.)

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Epidemiology

Cancer in Adults

Higher incidence in men > women

Men: Prostate, lung, colorectal 54%

Women: breast, lung, colorectal 52%

Cancer in Children

Leukemia

Lymphoma

Central nervous system tumors

Risk Factors

Smoking

High fat, low fiber diet

Obesity

Family history (breast cancer)

Age

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Etiologic Factors in Human Cancer

Environmental Factors

Chemicals, insecticides, fertilizers, herbicides

Radiation

Pollutants, air and water contamination, oil spills

Host Factors and Disease Associations

Immunodeficiencies

Immunosuppression

Neurofibromatosis

Cirrhosis

Chronic inflammatory bowel disease

Viruses

Epstein Barr Virus

Human Papilloma Virus

Hepatitis B

HIV

HTLV-I

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Stages of Carcinogenesis

Box 33-1

The Process of Cancer

Cancer is a multistep process involving:

Initiation (

irreversible mutations involving

proto-

oncogenesis

)

Promotion (growth enhancement to pass on the

mutation

to other cells)

Progression (e.g., development of tumor heterogeneity for metastasis, drug resistance)

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Cancer-Predisposing Genes

Cancer-predisposing genes may act in the following ways:

Affect the rate at which exogenous pre-carcinogens are metabolized to actively carcinogenic forms that can damage the cellular genome directly.

Affect’s a host’s ability to repair resulting damage to DNA

Alter the immune ability of the body to recognize and eradicate incipient tumors.

Affect the function of the apparatus responsible for the regulation of normal cell growth and associated proliferation of tissue

.

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Proto-oncogenes

p53 Protein

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Role Of Oncogenes

Mechanisms of Activation

Point mutations

Translocations

Gene amplification

Viral Oncogenes

Epstein Barr Virus

Human papilloma viruses

Tumor-Suppressing Genes

new discoveries of tumor suppressing

genes

Interferon IFN,

Transforming Growth Factor, TGF

Tumor Necrosis Factor, TNF

Help

downregulate

cell proliferation

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Body Defenses Against Cancer

T Lymphocytes: Cytotoxic T Lymphocytes (CTL)

Natural Killer (NK) Cells: Antibody mediated cellular cytotoxicity

Macrophages: secrete TNF toxic to tumor vasculature

Antibodies: bind to tumor associated antigens and serve as target for NK cells

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Tumor Markers

Categories of Tumor Antigens

Tumor-Specific Antigens: chemicals*

Tumor-Associated Antigens: viruses*

Oncofetal

Antigens: normally absent in adult tissue

Spontaneous Tumor Antigens

Specific Tumor Markers: CEA,,, PSA, AFP

Breast, Ovarian, and Cervical Cancer

Markers: CA

15-3,

CA

125, HER-2/

neu

Bladder Cancer Markers NMP-22, BTA

DNA microarray technology: signature patterns of certain cancers

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Modalities for Treating Cancer

Chemotherapeutic Agents

Cell cycle active

Non-cell cycle active

Effects of Drug-Induced Immunosuppression

Risk of infections

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Recent Advances

Immunotherapy

Mabs

-chemotherapy conjugates

Enhancement of Cell Mediated Immunity to tumors

Tumor Vaccines

Non-pathogenic virus carriers

Monoclonal antibodies (Herceptin,

Rituxan

,

Campath

, Erbitux

What’s New in Drug Therapy

Gleevec

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Chapter 31

Solid Organ Transplantation

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Introduction

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Chromosome 6

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Histocompatibility Antigens

Nomenclature of Human Leukocyte Antigen (HLA) Alleles

Role of Major Histocompatibility Complex (MHC) and HLAs

MHC Regions/Classes of HLA molecule

HLA Applications

Laboratory Evaluation of Potential Transplant Recipients and Donors

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Nomenclature

The HLA alleles are classified based on their function in coding for a certain antigen or a null allele (non coder).

The designations are agreed upon during international workshops or conventions where the discovery of new antigens are proposed.

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Role of MHC/HLAs

Between HLA ABC region and HLA-D region there is a group of genes (MHC class III genes) that code for complement proteins.

The LMP (large multifunctional protease) and the TAP (transporter associated with antigen presentation), are for antigen processing by the Antigen Presenting Cell (APC)

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Figure 31-01.

   Genetic organization of major histocompatibility complex

(MHC)

/HLA antigen.

LMP,

Large multifunctional protease;

TAP,

transporter associated with antigen presentation.

(From Nairn R, Helbert M:

Immunology for medical students

, ed 2, St Louis, 2007, Mosby.)

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Role of MHC/HLAs

The major role of the MHC complex is to provide a vehicle that carries the foreign antigen and presents it to the macrophage or dendritic cell

The HLA A,B and C regions are class I MHC genes code for molecules that present antigens to CD8

+

T cells

HLA D region has the class II MHC genes that code for molecules that present antigens to CD4

+

T cells

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CD4 T-helper cell

CD8 T suppressor cytotoxic

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Applications

HLA typing: HLA A, B and DR are the ones considered. Each individual has two of each. The best match is 6/6, the poorest is 0/6.

A potential kidney recipient will be checked for

Recipients age*

Cause for kidney failure*

Pre-transplantation blood transfusions*

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In bone marrow transplants, it is required to have a 6/6 match to reduce the chances for GVHD

A new approach removing the donor T cells, increases the chances for success greatly reducing the incidence of GVHD

Paternity testing: used to be ABO, Rh and MNS testing with a chance of 58% false positives.

Including HLA typing along with other RBC antigens MNS,

Kell

, Duffy, Kidd, have increase the certainty to 92%

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Some HLA antigens have been associated with disease*

HLA-B27 Ankylosing Spondylitis

HLA-DR4 Rheumatoid Arthritis

HLA-DR3 Type I Diabetes

HLA-B8 Celiac Disease,

Sjogren’s

Syndr

.

HLA-DR5 Scleroderma

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HLA Typing

Terasaki

microplates

Complement-Mediated Cytotoxicity.

Specific antisera + target cells + vital dye

Flow Cytometry

Target lymphocytes + antisera + anti-human IgG*

Microparticles

coated with recombinant HLA antigens

ELISA: antisera + recombinant HLA antigens

PCR: allele-specific primers

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Figure 31-02.

   Patients (recipients) requiring a solid organ transplant such as a kidney are human leukocyte antigen (HLA)–typed

(A)

and then placed on a transplant registry waiting list

(B).

(From Nairn R, Helbert M:

Immunology for medical students,

ed 2, St Louis, 2007, Mosby.)

Tranplantation

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When a potential organ becomes available, the donor is HLA–typed

(C).

If the donor and recipient demonstrate a suitable match by computer, a blood sample is procured from the donor and cross-matched with the recipient’s blood to determine compatibility. If no HLA antibodies are detected against the donor cells, the organ is harvested and transplanted to the recipient

(D).

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Facts about Solid Organ Transplant

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Transplantation Terminology

Table

31-6

Transplantation Terms

Term

Definition

Autograft

Graft transferred from one position to another in the same individual

(e.g., skin, hair, bone).

Syngraft

Graft transplanted between different but identical

recipient

and donor

(e.g., kidney transplant between monozygous twins).

Allograft

(homograft)

Graft between genetically different recipient and donor of the same species; the grafted donor tissue or organ contains antigens not present

In the recipient.

Xenograft

(heterograft)

Graft between individuals of different species (e.g., pig heart valve to a human heart)

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Types of Transplants

Kidney (high rate of success)

Heart Valves (Xenogeneic)

Heart 1967 Dr. Christian Barnard

Cornea (avascular)

Skin (high rate of rejection, immunosuppressive)

Liver

Lung (technically challenging)

Pancreas (limited success)

Bone

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Figure 31-03.

   People living with functioning graft (kidney, liver, heart, lung) at year end, 1996–2005.

(From OPTN/SRTR: 2006 annual report, Table 1.14.)

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Graft-versus-Host Disease

Etiology:

Epidemiology

Signs and Symptoms:

Immunologic Manifestations:

Diagnostic Evaluation

Prevention

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Etiology of GVHD

In an immunocompromised host, there is always a risk that the transplanted organ or bone marrow may have leukocytes that will recognize the hosts tissue as foreign and react against the host.

Instead of the host rejecting the graft, this is a situation that the graft is reacting against the host.

The lymphocytes coming with the graft undergo proliferation, cause inflammation, tissue damage and if not controlled it can cause death of recipient

.

The strongest the antigenic difference, the more severe the GVHD.*

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Epidemiology of GVHD

There is a high risk of GVHD whenever immunologically competent lymphocytes are introduced into an immunocompromised host.

Chronic GVHD affects 20% to 40% of patients six months post transplant

Age of recipient

History of previous GVHD

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Signs and Symptoms of GVHD

GVHD causes an inflammatory response

Similar to post transfusion symptoms, it starts in 3 to 30 days after transfusion

Lymphocytes infiltrate in the intestine, skin, liver; there is mucosal destruction, skin ulcerations, mouth lesions, diarrhea, liver destruction.

There is jaundice, fever, anemia, weight loss, skin rash, splenomegaly

Bone marrow GVHDD can occur in about 3 months post transplantation, starting with skin lesions, liver dysfunction, gastrointestinal tract inflammation.

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Frequently, there are problems with CMV infection*

New infection

reactivation

Complications with

granulocytopenia

, fever, bacteremia, interstitial pneumonia.

There is diarrhea with abdominal pain and liver disease.

Chronic GVHD resembles collagen disease with skin changes, erythema and ulcerations

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Immunologic Manifestations

Lymphocytes from transfusion or graft react with host tissue causing inflammation and systemic cell mediated damage

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Diagnostic Evaluation

Evidence of immunosuppression or immunodeficiency seen by the decrease in lymphocytes suggests GVHD

CRP, ESR, CBC, CMP

Blood cultures to check for bacteremia

Viral antigen assays

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Prevention

Elimination of mature lymphocytes from the graft with monoclonal antibodies helps reduce the risk.

Irradiation of blood products has been the most cost effective way to help prevent GVHD.

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Factors in Graft Rejection

Immunologic Tolerance

T-cell tolerance

B-cell tolerance

Immune Response Gene-Associated Antigens

Manipulation of the

Ir

gene, responsible for interaction between T and B cells

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Types of Graft Rejection

Hyperacute

Rejection*: mismatch

First set rejection: lymphocytes become sensitized to graft tissue antigens

Second set rejection: Lymphocyte cytotoxicity occurs faster, poor graft survival

Accelerated rejection: comparable to second set rejection

Acute Rejection: Host becomes sensitized to graft antigens, T lymphocytes begin the process and later antibody mediated damage occurs

Chronic Rejection: gradual rejection due to previous unsuccessful transplants; grafts may last years and they gradually become rejected.

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Figure 31-03.   Hyperacute rejection results from placement of tissue in an animal already possessing antibodies to antigens of grafted tissue. Second-set rejection is an accelerated first-set reaction and is seen in animals that have already rejected tissue at least once (Redrawn from Barrett JT: Textbook of immunology, ed 5, St Louis, 1988, Mosby.)

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Mechanisms of Rejection

General Characteristics

Role of T Cells

Antibody Effects

Immunosuppressive Protocols

Post–Organ Transplant Complications

Xenotransplantation

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Mechanisms of Rejection

General Characteristics: The expression of class II molecules and how much the APCs from the host have infiltrated the tissue influence the survival of the graft.

Role of T cells: recognition of class I molecules elicit cytotoxic activity. Activation of T-helper cells via class II molecules initiates antibody mediated reactions.

Antibody: Antibodies can bind to graft antigens and

Activate complement proteins

Opsonization

Antibody mediated cellular cytotoxicity

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Immunosuppression

Immunosuppression is critical to the success of the transplant.

Drugs

Cyclosporin

A: inhibits induction of cytotoxic T-cells

Steroids: inhibits antigen-driven T-cell proliferation

Azathioprine: inhibits purine nucleotide

synthesis

RNA

Anti lymphocyte globulin: enhances

antiallogeneic

antibodies

Radiation

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Post Transplant Complications

Infectious Disease

Cancer

Osteoporosis

Diabetes

Hypertension

Hypercholesterolemia

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Xenotransplantation

Due to shortage of organs for transplant.

Pig heart valves for human hearts and pancreatic tissue to treat diabetes

Pig is the preferred source, similarities to human tissue, size of organs is similar, low risk of pig tissue to infect human organs

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Biomarkers for Rejection

New molecular tools, gene profiling, etc., are progressing towards the development of better tools to diagnose tissue rejection.

Today it is still invasive by examining biopsy material.

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Chapter 32

Bone Marrow Transplantation

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Introduction

What is the goal of transplanting bone marrow or peripheral blood progenitor cells?

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Cancers Treated with Progenitor Cell Transplants

Leukemia

Non-Hodgkin’s and

Hodgkin’s Lymphoma

Severe Combined

Immunodeficies

CML

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What are Progenitor Blood Cells

?

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Progenitor Stem Cells

Very early hematopoietic cells have the ability to become any blood cell depending on the present demand and microenvironmental factors

They express CD34

Some circulate the peripheral blood: PBSC

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Types of Transplants

Table 31-4

Transplantation Terms

Term

Definition

Autograft

Graft transferred from one position to another in the same individual

(e.g., skin, hair, bone).

Syngraft

Graft transplanted between different but identical recent and donor

(e.g., kidney transplant between monozygous twins).

Allograft

(homograft)

Graft between genetically different recipient and donor of the same species; the grafted donor tissue or organ contains antigens not present

In the recipient.

Xenograft

(heterograft)

Graft between individuals of different species (e.g., pig heart valve to a human heart)

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Traditional Treatment Options

Chemotherapy

Radiotherapy

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Evaluation of Candidates for Peripheral Blood Stem Cell (PBSC)/Bone Marrow (BM)

Transplant

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Obtaining Cells for Transplant

Bone Marrow (BM)

Peripheral Blood Progenitor (Stem) Cells (PBSCs)

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Figure 32-02.

   Bone marrow harvest from posterior iliac crest.

(Courtesy Bone Marrow Transplant Unit, Massachusetts General Hospital, Boston.)

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Transplantation

Transplant-Related Complications

Infection

GVHD

Rejection & organ damage

First 100 days are critical

Manipulation and Storage of the Graft

Harvest and concentration of large volumes of marrow

Remove as much as the RBCs as possible in case recipient has antibodies to donor RBCs

Leukopheresis

machines

COBE

and Baxter

Cells are frozen with DMSO*

Infusion of Cells

DMSO in the infusion causes patients to feel a garlic-like taste

Infused cells travel to the bone marrow and there they will generate new cells

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Figure 32-03.

   COBE Spectra Apheresis System.

(Courtesy Gambro BCT, Lakewood, Colo.)

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Figure 32-04.

   Baxter Isolex 300i Magnetic Cell Selector.

(Courtesy Baxter, Deerfield, Ill.)

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Transplants from Unrelated Donors

The National Marrow Donor Program (NAMDP)

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Current Directions

Research: gene transfer, gene expression and hematopoietic manipulation.

ID and significance of minor HLA antigens.

Increase rate of transplant success

Donor leukocyte infusions.

Graft vs leukemia

Graft vs lymphoma

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Future Directions

Methods to deliver specific cell populations.

New immunosuppressive drugs.

Highly specific M Abs against lymphoma cells.

Non-myeloablative approach to chemotherapy

.