This document discusses immunology of transplantation and malignancy. It defines transplantation as transferring cells, tissues or organs from one site to another. The first- and second-set rejection of allografts is described, where a second graft from the same donor is rejected more quickly. Tumor cells can induce immune responses as they express new antigens foreign to the host. However, tumors can escape immunosurveillance through various mechanisms like weak immunogenicity or suppression of the immune response. Immunotherapy approaches aim to enhance these immune responses through both active and passive methods.
2. 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
6. 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
7. 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
10. 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)
11. 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
12. 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
13. 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
14. 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
15.
16. 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)
17. 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
18. Normal Cell Growth
Control of cell
growth
Growth-promoting
Proto-oncogenes
Growth-restricting
Tumor-suppressor
genes
19. Molecular Basis of Cancer
Uncontrolled
cell growth
Proto-oncogenes
Tumor-suppressor
genes
Mutations
Radiation
Chemical (Carcinogen)
Virus
20. Etiology of tumor
1) Inherited :
Expression of inherited oncogene
e.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
21. Tumour antigens
Major Histocompatability
Complex antigens
Tumor-specific
Antigens TSTA
(TSAs)
Tumor-associated
Antigens TATA
(TAAs)
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)
22. 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
23. 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)
24. 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
25. Natural Killer Cells
• 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
26. • 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
27.
28. Antibody Dependent Cell Mediated
Cytotoxicity (ADCC)
• 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)
29.
30.
31. 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
32. The mechanisms of such escape are not clear but
various possibilities have been suggested
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
35. 36
Escape from immunosurveillance
Tumors secrete immuno-suppressive
molecules
36. 37
Escape from immunosurveillance
Production of blocking
antibodies
37. 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
38. 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
39. 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)