1. Immunology of Transplantation
ad Malignancy
Dr. Pendru Raghunath Reddy

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

3. Can you imagine?

5. Applications of allografting transplantation

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

9. First- and second-set allograft rejection
Figure 16.1

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

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

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)

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

33. 34
Escape from immunosurveillance
Lack of neo-antigens

34. 35
Escape from immunosurveillance
Lack of class I MHC

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)