Endothelial

cell Blood

vessel

Alloantigen-specific

CD8+ T cell

Circulating

alloantigenspecific antibody

Complement activation,

endothelial damage,

inflammation

and thrombosis

Hyperacute rejection

Parenchymal cells

Endothelial

cell

Alloreactive

antibody

 Parenchymal cell damage, Acuterejection interstitial inflammation

Chronic rejection

Chronic inflammatory

 reaction in vessel wall,

 intimal smooth muscle

cell proliferation,

vessel occlusion

Alloantigenspecific CD4+

T cell

Vascular

smooth muscle cell

Cytokines

Cytokines

APC

Macrophage

Endothelialitis

B

A

Alloantigen

(e.g., blood group antigen)

i

ii

Fig. 10.13 Mechanisms and histopathology of graft rejection. A representative histologic appearance of

each type of rejection is shown on the right. A, In hyperacute rejection, preformed antibodies react with alloantigens on the vascular endothelium of the graft, activate complement, and trigger rapid intravascular thrombosis and necrosis of the vessel wall. B, In acute rejection, CD8+ T lymphocytes reactive with alloantigens

on graft endothelial cells and parenchymal cells or antibodies reactive with endothelial cells cause damage to

these cell types. Inflammation of the endothelium is called endothelialitis. The histology shows acute cellular

rejection in i and humoral (antibody-mediated) rejection in ii. C, In chronic rejection with graft arteriosclerosis,

T cells reactive with graft alloantigens may produce cytokines that induce inflammation and proliferation of

intimal smooth muscle cells, leading to luminal occlusion. APC, Antigen-presenting cells.

214 CHAPTER 10 Immunology of Tumors and Transplantation

clinical attempts to induce graft-specific tolerance have

not yet resulted in clinically practical methods.

A major problem in transplantation is the shortage of

suitable donor organs. Xenotransplantation has been

considered a possible solution for this problem. Experimental studies show that hyperacute rejection is a frequent cause of xenotransplant loss. The reasons for the

high incidence of hyperacute rejection of xenografts are

that individuals often contain antibodies that cross-react

with cells from other species and the xenograft cells

lack regulatory proteins that can inhibit human complement activation. These antibodies, similar to antibodies against blood group antigens, are called natural

antibodies because their production does not require

prior exposure to the xenoantigens. It is thought that

these antibodies are produced against bacteria that normally inhabit the gut and that the antibodies cross-react

with cells of other species. Xenografts also are subject to

Drug Mechanism of action

Cyclosporine

and tacrolimus

Mycophenolate

mofetil

Rapamycin

(sirolimus)

Blocks T cell cytokine

production by inhibiting

the phosphatase

calcineurin and thus

blocking activation of the

NFAT transcription factor

Blocks lymphocyte

proliferation by inhibiting

guanine nucleotide

synthesis in lymphocytes

Blocks lymphocyte

proliferation by inhibiting

mTOR and IL-2 signaling

Corticosteroids

Antithymocyte

globulin

Anti-IL-2

receptor

(CD25)

antibody

CTLA4-Ig

(belatacept)

Reduce inflammation

by effects on multiple

cell types

Binds to and depletes

T cells by promoting

phagocytosis or

complement-mediated

lysis (used to treat

acute rejection)

Inhibits T cell proliferation

by blocking IL-2 binding;

may also opsonize and

help eliminate activated

IL-2R-expressing T cells

Anti-CD52

(alemtuzumab)

Depletes lymphocytes by

complement-mediated

lysis

Inhibits T cell activation by

blocking B7 costimulator

binding to T cell CD28

Fig. 10.14 Treatments for graft rejection. Agents used to treat rejection of organ grafts and their mechanisms of action. Like cyclosporine, tacrolimus (FK506) is a calcineurin inhibitor. CTLA4-Ig, Cytotoxic T

lymphocyte–associated protein 4–immunoglobulin (fusion protein), not widely used; IL, interleukin; mTOR,

mammalian target of rapamycin; NFAT, nuclear factor of activated T cells.

CHAPTER 10 Immunology of Tumors and Transplantation 215

acute rejection, much like allografts but often even more

severe than rejection of allografts. Because of the problem of rejection, and difficulty in procuring organs from

animals that are evolutionarily close to humans, clinical

xenotransplantation remains a distant goal.

Transplantation of Blood Cells and

Hematopoietic Stem Cells

Transfer of blood cells between humans, called transfusion,

is the oldest form of transplantation in clinical medicine.

The major barrier to transfusion is the presence of allogeneic blood group antigens, the prototypes of which are the

ABO antigens (Fig. 10.15). These antigens are expressed on

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

ABO antigens are carbohydrates on membrane glycoproteins or glycosphingolipids; they contain a core glycan that

may be enzymatically modified by addition of either of two

types of terminal sugar residues. There are three alleles of

the gene encoding the enzyme that adds these sugars: one

encodes an enzyme that adds N-acetylgalactosamine, one

that adds galactose, and one that is inactive and cannot add

either. Therefore, depending on the alleles inherited, an

individual may be one of four different ABO blood groups:

Blood group A individuals have N-acetylgalactosamine

added to the core glycan; blood group B individuals have

a terminal galactose; blood group AB individuals express

both terminal sugars on different glycolipid or glycoprotein

molecules; and individuals with blood group O express the

core glycan without either of the terminal sugars.

Individuals are tolerant of the blood group antigens they

express, but make antibodies specific for the antigens they

do not express. Thus, type A individuals make anti-B antibodies, type B individuals make anti-A antibodies, O group

individuals make both anti-A and anti-B, and type AB individuals do not make anti-A or anti-B antibodies. These antibodies are called natural antibodies because they are made

in the absence of the antigen. They are likely produced by

B cells in response to antigens of intestinal microbes, and

the antibodies cross-react with ABO blood group antigens.

Because the blood group antigens are sugars, they do not

elicit T cell responses that drive isotype switching, and the

antibodies specific for A or B antigens are largely IgM. The

preformed antibodies react against transfused blood cells

expressing the target antigens and activate complement,

which lyses the red cells; the result may be a severe transfusion reaction, characterized by a strong systemic inflammatory response, intravascular thrombosis, and kidney

damage. This problem is avoided by matching blood donors

and recipients so there are no antigens on the donor cells

that can be recognized by preformed antibodies in the recipient, a standard practice in medicine.

Blood group antigens other than the ABO antigens also

are involved in transfusion reactions, and these usually are

less severe. One important example is the RhD antigen,

which is a red cell membrane protein expressed by about

90% of people. Pregnant women who are RhD-negative

can be immunized by exposure to RhD-expressing red

cells from the baby during childbirth if the baby inherited

the RhD gene from the father. The mother will produce

anti-RhD antibodies that can cross the placenta during

subsequent pregnancies and attack Rh-positive fetal cells,

causing hemolytic disease of the fetus and newborn.

Hematopoietic stem cell transplantation is being

used increasingly to correct hematopoietic defects, to

restore bone marrow cells damaged by irradiation and

chemotherapy for cancer, and to treat leukemias. Either

bone marrow cells or, more often, hematopoietic stem

cells mobilized in a donor’s blood are injected into the circulation of a recipient, and the cells home to the marrow.

The transplantation of hematopoietic stem cells poses

many special problems. Before transplantation, some of

the bone marrow of the recipient has to be destroyed to

create space to receive the transplanted stem cells, and

this depletion of the recipient’s marrow inevitably causes

deficiency of blood cells, including immune cells, resulting in potentially serious immune deficiencies before the

transplanted stem cells generate enough replacement

blood cells. The immune system reacts strongly against

allogeneic hematopoietic stem cells, so successful transplantation requires careful HLA matching of donor

and recipient. HLA matching also prevents rejection of

transplanted stem cells by NK cells, which are inhibited

by recognition of self MHC molecules (see Chapter 2). If

mature allogeneic T cells are transplanted with the stem

cells, these mature T cells can attack the recipient’s tissues,

resulting in a clinical reaction called graft-versus-host

disease. When the donor is an HLA-identical sibling (as

in about 80% of cases), this reaction is directed against

minor histocompatibility antigens. The same reaction is

exploited to kill leukemia cells (so-called graft-versusleukemia effect), and hematopoietic stem cell transplantation is now commonly used to treat leukemias resistant

to chemotherapy. NK cells in the marrow inoculum may

also contribute to the destruction of leukemia cells.

Despite these problems, hematopoietic stem cell

transplantation is a successful therapy for a wide variety

of diseases affecting the hematopoietic and lymphoid

systems.

216 CHAPTER 10 Immunology of Tumors and Transplantation

SUMMARY

• The adaptive immune system is able to eradicate or

prevent the growth of tumors.

• Tumors may induce antibody, CD4+ T cell, and CD8+

T cell responses, but CD8+ CTL killing of tumor cells

appears to be the most important antitumor effector

mechanism.

• Most cancer antigens that induce T cell responses are

neoantigens encoded by randomly mutated genes

(passenger mutations), which do not contribute to

the malignant phenotype of the cancer cells. Other

tumor antigens include products of oncogenes and

tumor suppressor genes, overexpressed or aberrantly

expressed structurally normal molecules, and products of oncogenic viruses.

• CTLs recognize mutant peptides derived from tumor

antigens displayed by class I MHC molecules. The

induction of CTL responses against tumor antigens

involves ingestion of tumor cells or their antigens

by dendritic cells, cross-presentation of the antigens

to naïve CD8+ T cells, activation of the T cells and

differentiation into CTLs, CTL migration from the

blood into tumors, CTL recognition of the tumor

antigens on the tumor cells, and killing of the tumor

cells.

• Tumors may evade immune responses by losing

expression of their antigens, shutting off expression of MHC molecules or molecules involved in

antigen processing, expressing ligands for T cell

inhibitory receptors, and inducing regulatory T

cells or secreting cytokines that suppress immune

responses.

B

A

Group A Group B Group AB Group O

Red blood

cell type

Antibodies

present

Antigens

present

Anti-B Anti-A None Anti-A and Anti-B

A antigen B antigen A and B antigen None

Type A Type B Type AB Type O

N acetylgalactosamine

N acetylglucosamine

Fucose

Galactose

A O B

Fig. 10.15 ABO blood group antigens. A, Chemical structure of ABO antigens. B, Figure shows the antigens and antibodies

present in people with the major ABO blood groups.

CHAPTER 10 Immunology of Tumors and Transplantation 217

• CAR-T cell immunotherapy is another breakthrough

approach now in clinical practice. CAR-T cells are generated in vitro by transducing a cancer patient’s T cells

to express a recombinant receptor with an antibody-like

binding site for a tumor antigen and a cytoplasmic tail

with potent signaling functions. Adoptive transfer of

CAR-T cells back into patients has been successful in

treating B-cell–derived leukemias and lymphomas.

• Immune checkpoint blockade is the major cancer

immunotherapy strategy in current practice. Monoclonal antibodies that block the function of T cell

inhibitory molecules, such as CTLA-4 and PD-1, are

injected into the patient, which enhances the activation of tumor-specific T cells by tumor antigens.

This approach has been highly successful in treating

patients with many kinds of advanced cancers, but

more than 50% of patients do not respond, and many

patients develop autoimmune side effects.

• Personalized neoantigen vaccines are now in clinical

trials. The creation of these vaccines relies on cancer

genome sequencing to identify neoantigen peptides

unique to an individual patient’s tumor, which bind

to that patient’s MHC molecules.

• Organ and tissue transplantation from one individual

to another is widely used to treat many diseases, but a

major barrier to successful transplantation of foreign

tissues is rejection by adaptive immune responses,

including CD8+ CTLs, CD4+ helper T cells, and antibodies.

• The most important antigens that stimulate graft rejection are allogeneic MHC molecules, which resemble

peptide-loaded self MHC molecules that the graft

recipient’s T cells can recognize. Allogeneic MHC

molecules are either presented by graft APCs without

processing to recipient T cells (direct presentation), or

are processed and presented as peptides bound to self

MHC by host APCs (indirect presentation).

• Grafts may be rejected by different mechanisms. Hyperacute rejection is mediated by preformed antibodies to

blood group antigens or HLA molecules, which cause

endothelial injury and thrombosis of blood vessels in the

graft. Acute rejection is mediated by T cells, which injure

graft cells and endothelium, and by antibodies that bind

to the endothelium. Chronic rejection is caused by T

cells that produce cytokines that stimulate growth of

vascular smooth muscle cells and tissue fibroblasts.

• Treatment for graft rejection is designed to suppress

T cell responses and inflammation. The mainstay

of treatment has been immunosuppressive drugs,

including corticosteroids and calcineurin inhibitors,

mTOR inhibitors, antimetabolites, and many others.

• Blood cell transfusion is the oldest and most widely

used form of transplantation and requires ABO

blood group compatibility of donor and recipient.

ABO blood group antigens are sugars expressed on

the surfaces of red blood cells, endothelial cells, and

other cells, and people produce natural antibodies

specific for the ABO antigens they do not express.

• Hematopoietic stem cell transplants are widely used

to treat cancers of blood cells and to replace defective

components of the immune or hematopoietic system.

These cell transplants elicit strong rejection reactions,

carry the risk of graft-versus-host disease, and often

lead to temporary immunodeficiency in recipients.

REVIEW QUESTIONS

1. What are the main types of tumor antigens that the

immune system reacts against?

2. What is the evidence that tumor rejection is an

immunologic phenomenon?

3. How do naive CD8+ T cells recognize tumor antigens, and how are these cells activated to differentiate

into effector CTLs?

4. What are some of the mechanisms by which tumors

may evade the immune response?

5. What are some strategies for enhancing host immune

responses to tumor antigens?

6. Why do normal T cells, which recognize foreign peptide antigens bound to self MHC molecules, react

strongly against the allogeneic MHC molecules of a

graft?

7. What are the principal mechanisms of rejection of

allografts?

8. How is the likelihood of graft rejection reduced in

clinical transplantation?

9. What are some of the problems associated with the

transplantation of hematopoietic stem cells?

Answers to and discussion of the Review Questions are

available at Student Consult.

218

Disorders Caused by

Immune Responses

11

The concept that the immune system is required for

defending the host against infections has been emphasized throughout this book. However, immune responses

are themselves capable of causing tissue injury and disease. Injurious, or pathologic, immune reactions are

called hypersensitivity reactions. An immune response

to an antigen may result not only in protective immunity

but also a detectable reaction to challenge with that antigen, called sensitivity, and therefore hypersensitivity is

a reflection of excessive or aberrant immune responses.

Hypersensitivity reactions may occur in two situations.

First, responses to foreign antigens (microbes and noninfectious environmental antigens) may cause tissue

injury, especially if the reactions are repetitive or poorly

controlled. Second, the immune responses may be

directed against self (autologous) antigens, as a result of

the failure of self-tolerance (see Chapter 9). Responses

against self antigens are termed autoimmunity, and disorders caused by such responses are called autoimmune

diseases.

This chapter describes the important features of

hypersensitivity reactions and the resulting diseases,

focusing on their pathogenesis. Their clinicopathologic

features are described only briefly and can be found in

other medical textbooks. The following questions are

addressed:

• What are the mechanisms of different types of hypersensitivity reactions?

• What are the major clinical and pathologic features of diseases caused by these reactions?

• What principles underlie treatment of such diseases?

Hypersensitivity

CHAPTER OUTLINE

Types of Hypersensitivity Reactions, 219

Immediate Hypersensitivity, 219

Activation of Th2 Cells and Production of IgE

Antibody, 219

Activation of Mast Cells and Secretion of Mediators, 222

Clinical Syndromes and Therapy, 224

Diseases Caused by Antibodies Specific for Cell and

Tissue Antigens, 225

Mechanisms of Antibody-Mediated Tissue Injury

and Disease, 226

Examples and Treatment of Diseases Caused by

Cell- or Tissue-Specific Antibodies, 228

Diseases Caused by Antigen-Antibody

Complexes, 229

Etiology, Examples, and Therapy of Immune

Complex–Mediated Diseases, 230

Diseases Caused by T Lymphocytes, 230

Etiology of T Cell–Mediated Diseases, 230

Mechanisms of Tissue Injury, 231

Clinical Syndromes and Therapy, 232

Neuroimmunology: Interactions Between the

Immune and Nervous Systems, 232

Summary, 234

CHAPTER 11 Hypersensitivity 219

TYPES OF HYPERSENSITIVITY

REACTIONS

Hypersensitivity reactions are classified on the basis of

the principal immunologic mechanism that is responsible for tissue injury and disease (Fig. 11.1). We will

use the informative descriptive classifications throughout this chapter, but we will also indicate the numerical

designations for each type since they are widely used.

• Immediate hypersensitivity, or type I hypersensitivity, is a type of pathologic reaction that is caused by

the release of mediators from mast cells. This reaction most often depends on the production of immunoglobulin E (IgE) antibody against environmental

antigens and the binding of IgE to mast cells in various tissues.

• Antibodies that are directed against cell or tissue

antigens can damage these cells or tissues or can

impair their function. These diseases are said to be

antibody mediated or type II hypersensitivity.

• Antibodies against soluble antigens in the blood may

form complexes with the antigens, and the immune

complexes may deposit in blood vessels in various

tissues, causing inflammation and tissue injury. Such

disorders are called immune complex diseases or

type III hypersensitivity.

• Some diseases result from the reactions of T lymphocytes specific for self antigens or microbes in tissues.

These are T cell–mediated diseases or type IV hypersensitivity.

This classification scheme is useful because it distinguishes the mechanisms of immune-mediated tissue

injury. In many human immunologic diseases, however,

the damage may result from a combination of antibody-mediated and T cell–mediated reactions, so it is

often difficult to classify these diseases neatly into one

type of hypersensitivity.

IMMEDIATE HYPERSENSITIVITY

Immediate hypersensitivity is an IgE antibody– and

mast cell–mediated reaction to certain antigens that

causes rapid vascular leakage and mucosal secretions,

often followed by inflammation. Disorders in which

IgE-mediated immediate hypersensitivity is prominent

are also called allergy, or atopy, and individuals with

a propensity to develop these reactions are said to be

atopic. Immediate hypersensitivity may affect various

tissues and may be of varying severity in different individuals. Common types of allergies include hay fever,

food allergies, asthma, and anaphylaxis. Allergies are

the most frequent disorders of the immune system, estimated to affect 10% to 20% of people, and the incidence

of allergic diseases has been increasing, especially in

industrialized societies.

The sequence of events in the development of

immediate hypersensitivity reactions includes: activation of Th2 and IL-4–secreting follicular helper

T (Tfh) cells, which stimulate the production of IgE

antibodies in response to an antigen; binding of the

IgE to IgE-specific Fc receptors of mast cells; on subsequent exposure to the antigen, cross-linking of the

bound IgE by the antigen, leading to activation of

the mast cells and release of various mediators (Fig.

11.2). Some mast cell mediators cause a rapid increase in

vascular permeability and smooth muscle contraction,

resulting in many of the symptoms of these reactions

(Fig. 11.3). This vascular and smooth muscle reaction

may occur within minutes of reintroduction of antigen

into a previously sensitized individual, hence the name

immediate hypersensitivity. Other mast cell mediators

are cytokines that recruit neutrophils and eosinophils to

the site of the reaction over several hours. This inflammatory component is called the late-phase reaction, and

it is mainly responsible for the tissue injury that results

from repeated bouts of immediate hypersensitivity.

With this background, we proceed to a discussion of

the steps in immediate hypersensitivity reactions.

Activation of Th2 Cells and Production of IgE

Antibody

In individuals who are prone to allergies, exposure

to some antigens results in the activation of Th2

cells and IL-4–secreting Tfh cells, and the production of IgE antibody (see Fig. 11.2). Most individuals

do not mount strong Th2 responses to environmental antigens. For unknown reasons, when some individuals encounter certain antigens, such as proteins

in pollen, certain foods, insect venoms, or animal

dander, or if they are treated with certain drugs such

as penicillin, there is a strong Th2 response. Immediate hypersensitivity develops as a consequence of

the activation of Th2 and IL-4-secreting Tfh cells in

response to protein antigens or chemicals that bind

to proteins. Antigens that elicit immediate hypersensitivity (allergic) reactions often are called allergens.

220 CHAPTER 11 Hypersensitivity