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Chapter 10 – ImmuneResponses against

Tumors andTransplants

Dr. Hafez Sumairi

Learning outcomes

1.What are the antigens in tumors and tissuetransplants that are recognized as foreign by theimmune system?

2.How does the immune system recognize and reactto tumors and transplants?

3.How can immune responses to tumors and grafts bemanipulated to enhance tumor rejection and inhibitgraft rejection?

Immune responsesagainst tumors• Immune surveillance

Control and elimination ofmalignant cells by theimmune system

Tumor antigens• Malignant tumors

express various types ofmolecules that may berecognized by theimmune system asforeign antigens

Immune mechanisms of tumor rejection• The principal immune mechanism

of tumor eradication is killing oftumor cells by CTLs specific fortumor antigens.

• CTL responses against tumors oftenare induced by recognition of tumorantigens on host antigen-presentingcells (APCs)

• Cross-presentation or cross-priming, when one cell type (thedendritic cell) presents antigens ofanother cell (the tumor cell) andactivates (or primes) CD8+ Tlymphocytes specific for the secondcell type.

Evasion of immuneresponses by tumors• Immune responses often fail to check

tumor growth because tumors evolvein the host to evade immunerecognition or resist immune effectormechanisms.

• Tumors can grow rapidly• Tumor antigens are weakly

immunogenic.

• Tumor cells develop severalmechanisms of resistance to immunerecognition and destruction

Immunologicapproaches forcancer therapy• The main strategies for cancer

immunotherapy aim to

1. Provide antitumor effectors(antibodies and T cells) topatients

2. Actively immunize patientsagainst their tumors

3. Stimulate the patients′ ownantitumor immune responses

Immune responses against transplants

Donor is the individual that provides the graft

Recipient or host is the individual in whom thegraft is placed

Syngeneic are animals that are identical to oneanother (and grafts exchanged among theseanimals) isograft

Allogeneic (allografts) are animals (and grafts)of one species that differ from other animals ofthe same species

Xenogeneic (xenografts) are animals (andgrafts) of different species

Alloantigens & xenoantigens are the antigensthat serve as the targets of rejection

Alloreactive and xenoreactive are theantibodies and T cells that react against theseantigens

Transplantation antigens• The antigens of allografts that

serve as the principal targets ofrejection are proteins encoded inthe MHC

• MHC is called the humanleukocyte antigen (HLA) complex

• MHC genes are highlypolymorphic

• MHC proteins are the majorantigens that stimulate graftrejection

• Non-MHC antigens that inducegraft rejection are called minorhistocompatibility antigens

• Blood transfusion• Stem cell transplantation

Induction of immune responses against transplants

• Direct recognition (or directpresentation) T cells mayrecognize allogeneic MHCmolecules in the graft displayedby donor dendritic cells in thegraft

• Indirect recognition (orindirect presentation) Graftalloantigens may be processedand presented by the host′sdendritic cells

• Mixed lymphocyte reaction(MLR) is an in vitro model of Tcell recognition of alloantigens

Immune mechanismsof graft rejectionGraft rejection is classified into hyperacute,acute, and chronic, on the basis of clinical andpathologic features

• Hyperacute rejection occurs within minutesof transplantation, is mediated by circulatingantibodies and is characterized by thrombosisof graft vessels and ischemic necrosis of thegraft

• Acute rejection occurs within days or weeksafter transplantation, is mediated by T cellsand antibodies leading to vascular damage

• Chronic rejection is occur over months oryears, leading to progressive loss of graftfunction, manifested as fibrosis & graftarteriosclerosis

Prevention and treatment ofgraft rejection• The mainstay of preventing and

treating the rejection of organtransplants is immunosuppression,designed mainly to inhibit T cellactivation and effector functions

1. Block cytokine production2. Block lymphocyte proliferation3. Reduce inflammation4. Bind to & deplete T cell5. Inhibit T cell activation

Transplantation ofblood cells andhematopoietic stemcells (transfusion)• These antigens are expressed on

red blood cells, endothelial cells,and many other cell types

• Transfusion reaction

• Blood group antigens are sugars,they do not elicit T cell responses

• Rh antigen, which is a red cellmembrane protein

• Hematopoietic stem celltransplantation

• HLA matching

• Graft-versus-host disease

Maternal tolerance to fetal tissues

• The anatomy of the trophoblast and placenta plays a key role intolerance to the fetus

• Placenta• Does not allow T cells to enter• Actively suppresses immune responses by the action of abundant regulatory T cells or

immunosuppressive molecules

• Maternal trophoblast• Expresses low levels of conventional class I MHC molecules• Expresses unique atypical class I MHC molecules which likely prevent maternal NK cell

recognition and attack

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