Immunology of Transplantation

ad Malignancy

Dr. Pendru Raghunath Reddy

Definition

Transplantation refers to the act of transferring cells, tissues or

organs from one site to another

The tissue or organ trasplanted is known as the transplant or

graft

The individual from whom the transplant is obtained is known as

the donor and the individual to whom it is applied, the recipient

or host

Can you imagine?

Applications of allografting transplantation

Allograft reaction

Rejection of the graft by the recipient is called the allograft

reaction

First set reponse

When a skin graft from an animal is applied on a genetically

unrelated animal of the same species, the graft appears to be

accepted initially

The graft is vascularized and seems morphologically and

functionally healthy during the first two or three days

By about the fourth day, inflammation becomes evident

The graft assumes a scab-like appearance with extending

necrosis and sloughs off by the the tenth day

Second set reponse

When a second allograft from the same donor is applied on a

sensitised recipient, it will be rejected in an accelerated fashion

Necrosis sets in early and the graft sloughs off by the sixth day

Antibodies play a dominant role along with cell mediated

immunity

First- and second-set allograft rejection

Figure 16.1

For matching donor and recipient for transplantation following

procedures are undertaken

1. ABO grouping

2. Tissue typing (detection of MHC antigens)

(Microcytotoxicity test, Mixed lymphocytes culture (MLC)

and Molecular methods)

Prevention of graft rejection

1. Immunosupression

2. Transplantation in anatomically protected (privilieged) sites

There are certain privileged sites where allografts are permitted

to survive

Examples: Cornea, Brain, Cartilage, Pancreatic islet cells

Fetus as allograft

The fetus can be considered an intrauterine allograft as it

contains antigens which are foreign to the mother

The reason why the fetus is exempted from rejection is not clear,

though many explanations have been offered

1. The palcenta acts as an immunological barrier

2. Mucoproteins

3. Blocking antibodies

4. MHC antigens

5. Alpha fetoprotein

6. β1- glycoprotein

Graft-Versus Host (GVH) reaction

Graft rejection is generally due to the reaction of the host to

grafted tissue (host-versus-graft response)

Contrary to that, the graft may mount an immune response

against the antigens of the host, this is known as

“graft-versus-host reaction”

The GVH reaction occurs when the following conditions are

present

1. The graft contains immunocompetent T cells

2. The recipient possesses HLA antigens that are absent in the

graft

3. The recipient must not reject the graft

The GVH reactions are predominantly cell mediated

GVH is a major complication of bone marrow transplantation

and affects 50 to 70% of bone marrow transplant patients

Donor T cells recognise alloantigens on the host cells

The activation and proliferation of these T cells and the

subsequent production of cytokines generate inflammatory

reactions in the skin, gastrointestinal tract and liver

The clinical manifestations of GVH reaction consists of

splenomegaly, fever, rash, anaemia, weight loss and

sometimes death

The clinical manifestations of GVH reaction in animals are

retardation of growth, emaciation, diarrhea, hepatosplenomegaly,

lymphoid atrophy and anaemia,terminating fatally

(runting disease)

Tumour immunity

When a cell undergoes malignant transformation, it expresses

new surface antigens and may also lose some normal antigens

The tumour associated antigens are immunologically distinct

from normal tissue antigens

Therefore, tumour can be considered as an allograft and is

expected to induce an immune response

Normal Cell Growth

Control of cell

growth

Growth-promotingProto-oncogenes

Growth-restrictingTumor-suppressor genes

Molecular Basis of Cancer

Uncontrolled

cell growth

Proto-oncogenesTumor-suppressor genes

MutationsRadiationChemical (Carcinogen)Virus

Etiology of tumor1) Inherited :

Expression of inherited oncogenee.g. viral gene incorporated into host gene

2) Viral:- Human papilloma, herpes type 2, HBV, EBV (DNA)- Human T-cell leuckemia virus (RNA)

3) Chemical:- Poly cyclic hydrocarbons cause sarcomas- Aromatic amines cause mammary carcinoma - Alkyl nitroso amines cause hepatoma

4) Radiological: Ultraviolet & ionizing irradiation

5) Spontaneous: failure in the cellular growth control

Tumour antigens

Major HistocompatabilityComplex antigens

TSTA

TATA

TSTA: unique to a tumor Play an important role in tumor rejection.TATA: shared by normal and tumor cells

Tumor-associated developmental Ag (TADA)Tumor-associated viral Ag (TAVA)

Tumor-specific

Antigens (TSAs)

Tumor-associated

Antigens (TAAs)

Tumour specific antigens (TSAs or TSTAs)

Unique to tumour cells and do not occur on normal cells in the

body

TSAs or TSTAs have been identified on tumours induced with

chemical or physical carcinogens and on some virally induced

tumours

In chemically induced tumors, these antigens are tumour

specific

Different tumours possess different antigens, even if they are

induced by the same carcinogen

In contrast, the TSAs of virus induced tumours are virus specific

Tumour associated antigens (TAA or TATAs)

These are present on tumour cells and also on some normal

cells

However, they are expressed at extremely low levels on normal

cells but are expressed at much higher levels on tumour cells

They fall into three categories

1. Tumour associated carbohydrate antigens (TACAs)

(Mucin-associated antigen detected in pancreatic and breast

cancers)

2. Oncofetal antigens

alphafetoprotein in hepatoma,

carcinoembryonic antigen (CEA) in colonic cancer)

3. Differentiation antigens (PSA in prostatic cancer)

Immune response in malignancy

Tumour antigens can induce both humoral and cell mediated

immune responses that result in the destruction of the

tumour cells

The immune response to tumour includes CTL-mediated lysis,

NK-cell activity, macrophage-mediated tumour destruction

and destruction mediated by ADCC

• NK Make up 5-10% of circulating lymphocytes

– Major producers of IFN

– Through IFN they influence innate immunity (M)

– They also influence adaptive immunity by favoring TH1

– Eliminate viruses and tumor cells

• Early responders to viral Infections

– IFN and IFN stimulates NK activity

– IFN production induces M to make IL-12

– IL-12 results in more IFN pushing towards TH1

– TH1 through IL-2 Induces CTL activation

Natural Killer Cells

• NK eliminate target cells same way as CTLs

– Through perforin/granzyme and FasL/Fas

• However they are different from CTLs

– No Ag specific TCR

– No CD3

– No MHC restriction

– No memory, same intensity regardless of repeated

exposure

• Cells capable of cytotoxicity express Fc receptors

• Antibody binds to target Cell, cytotoxic cells bind Fc portion of antibody

• Antibody provides the specificity

• Examples of cells capable of ADCC

– M, NK, Neutrophils, eosinophils

• Killing of target is accomplished

– Through perforin, granzyme (NK, Eosinophils)

– TNF (M, NK)

– Lytic enzymes (M, Neutrophils, Eosinophils, NK)

Antibody Dependent Cell Mediated

Cytotoxicity (ADCC)

Immunosurveillance

It is believed that malignant cells arise by mutation of somatic

cells

The immune system keeps a consant vigilance on these

malignant mutation of somatic cells and destroy them on the

spot

The development of tumours represents an escape from this

surveillance

1. Weak immunogenicity

2. Modulation of surface antigens

3. Masking tumour antigens

4. Supression of CMI

5. Fast rate of proliferation of malignant cells

6. Production of blocking antiodies

7. Low levels of HLA class I molecules

The mechanisms of such escape are not clear but

various possibilities have been suggested

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Escape from immunosurveillance

Lack of neo-antigens

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Escape from immunosurveillance

Lack of class I MHC

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Escape from immunosurveillance

Tumors secrete immuno-

suppressive molecules

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Escape from immunosurveillance

Production of blocking

antibodies

Immunotherapy of cancer

Different approaches have been attempted in the immunotherapy

of cancer

1. Active

a) Nonspecific

b) Specific

2. Passive

a) Nonspecific

b) Specific

c) Combined

Nonspecific active immunotherapy

Biological response modifiers (BRMs) are used to enhance

immune responses to tumours and fall into four major groups

1. Bacterial products

(BCG, nonliving Corynebacterium parvum)

2. Synthetic molecules

(Glucan, levamisole)

3. Cytokines

4. Hormones

Specific active immunotherapy

Specific active immunotherapy includes therapeutic vaccines of

tumour cells, cell extracts, purified or recombinant antigens,

peptides, heat shock proteins, or DNA antigen-pulsed dendritic

cells

Passive immunotherapy

Passive immunotherapy may be

1. Nonspecific (LAK cells)

2. Specific (antibodies alone or coupled to drugs, prodrugs, toxins

or radioisotope, bispecific antibodies T cells)

3. Combined (LAK cells and bispecific antibody)