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Dr. Faria Ashraf
Asst Professor

 Transfer of cells, tissues or organs from one individual
to another or from one site in the same individual is
known as Transplantation.
 The individual from whom the transplant is obtained is
known as Donor.
 The individual to whom it is applied is known as
Recipient.

1. Autograft: organ or tissue taken from one person and
grafted on the same person.
2. Isograft: a graft taken from an individual and
introduce into another individual of the same genetic
constitution. Eg. Identical twins.
3. Allograft (homograft): graft between two
genetically non-identical members of the same
species.
4. Xenograft (heterograft): graft between members of
different species.
5. Cadaver organ transplant

 Primary function of the immune system is to recognise
and eliminate foreign cells and antigens that enter the
body.
 Tissues and organs grafted from one individual to
another member of the same species (allograft) are
recognised as foreign and rejected. The name
‘histocompatibility complex’ came to be because its
discovery was based on transplantation.

 Human MHC antigens are therefore synonymous with
human leukocyte antigens (HLA).
 MHC complex is a system of cell antigens that are
responsible for allograft acceptance or rejection.

First Set Response
 Skin graft from a
genetically
unrelated
animal of same species
 Initial acceptance first
2-3 days, by about fourth day
inflammation and graft is
invaded by lymphocytes and
macrophages.
 Thrombosed
and necrosed
 Mainly by
T lymphocytes
 By 10th day graft sloughs off.

 If an individual has rejected a
graft by the first set response,
another graft from the same
donor is applied – rejected in
an accelerated manner.
 Necrosis sets early and graft
sloughs off by 6th day.
 Mainly by antibodies and cell
mediated immunity.

 Hyperacute rejection
 Acute rejection
 Chronic rejection

 WHITE GRAFT RESPONSE
Pre-existing specific antibodies in high titres in the
host circulation bind to donor endothelial antigens on the
donor tissue or organ.
Activates Complement Cascade
Characterized by thrombotic occlusion of graft
 Graft remains pale
 Rejected within minutes or hours, even without an
attempt at vascularization.
 Examples: Previous transplantation, blood transfusion
or pregnancy.

 1. Preformed Ab, 2. complement activation,
 3. neutrophil margination, 4. inflammation,
 5. Thrombosis formation

 Rejection occur within a week to 10 days after a
transplant has been grafted.
 This type of rejection is due to incompatibility of
allograft.
 The immune response against the graft increase in
intensity, with the accumulation of lymphocytes,
plasma cells, macrophages and neutrophils, leading to
endothelial damage. There is necrosis and edema and
finally graft rejected.
 Cell mediated immunity plays a role in this type of
rejection.

 T-cell, macrophage and Ab mediated,
myocyte and endothelial damage,
Inflammation

 Occurs in most solid organ transplants
Heart, Kidney, Lung, Liver
Characterized by:
 fibrosis
 vascular abnormalities
 loss of graft function over a prolonged period rejection
occur after 60 days or more.
 Both humoral and cell mediated immunity plays a role
in this type of rejection.
 Such patients respond poorly to corticosteroids.

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 Graft rejection is caused principally by a T cell-mediated immune response
to alloantigens expressed on the graft cells, primarily the MHC molecules.
 Peptides present in the groove of allogeneic:
 Class I MHC molecules - derived from proteins synthesized within the
allogeneic cell.
 Class II MHC molecules – are proteins taken up and processed by the
allogeneic APCs.

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 The process of graft rejection can be divided into two stages:
 Sensitization phase- which involves alloantigen (mainly graft MHC
molecules) presentation to recipient’s T cells
 Effector stage - which immune destruction of the graft takes place due
to activation of recipient’s T cells.

TRANSPLANTATION AND TUMOUR IMMUNITY (1).pptx

 Graft rejection is due to the reaction of the host to the
grafted tissue (host-versus-graft response). The graft
mounts an immune response against the antigens of the
host. This is known as the graft versus host reaction.
 This is common in stem cell therapy in bone marrow
transplants.
 GVH disease is of 2 types-
i) Acute: within 100 days after transplantation
ii) Chronic: after 100 days of transplantation.
They are graded on the basis of the severity and tissue
affected.

i) The recipient possesses transplantation antigens that
are absent in the graft.
ii) The graft contains immunocompetent T cells.
iii) The recipient is incapable of mounting an effective
response to eliminate the graft immunocompetent
cells.

 The acute or fulminant form of the disease (GVH) is
normally observed within first 10- 100 days post
transplant.
 GVH reactions are predominantly cell mediated. The
manifestations of GVH reaction consist of splenomegaly,
fever, rash, anaemia,weight loss and sometimes death.
 Neonatally thymectomisd animal receiving an allograft
of spleen or blood lymphocytes do not grow normally
but develop a fatal wasting syndrome.This syndrome is
known as Runt disease.

1. Histocompatibility Testing:
a. Blood grouping : ABO Blood group compatibility.
b. HLA compatibility:
-HLA typing
-Microcytotoxicity test
-Molecular methods
RFLP with southern blotting
PCR using sequence specific primers
2. Tissue Matching:
-mixed lymphocyte reaction or
culture

22
 Hyperacute rejection manifests severely and within minutes, and so the
treatment indicated is- immediate removal of the tissue.
 Chronic rejection is generally considered irreversible and poorly amenable
to treatment—only re-transplant generally indicated if feasible—though
inhaled cyclosporine is being investigated to delay or prevent chronic
rejection of lung transplants.

23
 Acute rejection is treated with therapeutic regimens consisting of one or
combination of various immunosuppressive therapies.

24
Immunosuppressive drugs:
Corticosteroids Prednisolone, hydrocortisone
Calcineurin inhibitors Cyclosporine, Tacrolimus
Mitotic inhibitors Azathioprine
Cyclophosphamide
Methotrexate
Anti-proliferatives Mycophenolic acid
mTOR inhibitor (mammalian
target of rapamycin)
Sirolimus (rapamycin)
Everolimus

25
 Two types of tumour antigens have been identified on tumor cells:
 Tumour-specific transplantation antigens (TSTA)
 Tumour-associated transplantation antigens (TATA)

Essentials of Medical Microbiology by Apurba S Sastry © Jaypee Brothers Medical Publishers
Tumour-specific Transplantation
Antigen
26
▰ Tumour-specific antigens are present only on tumour cells and are absent
in normal cells of the body.
▰ May result from mutations in tumour cells that generate altered cellular
proteins.
▰ Such tumour specific antigens reject tumour transplants in immunised
hosts, these are termed as tumour specific transplantation antigens.

Antigen (Cont..)
27
▰ TSTA are induced on tumour cells either by chemical or by physical
carcinogens, and also by viral carcinogens.
▰ Tumour specific.
▰ Methyl cholanthrene and ultraviolet light are the examples of chemical and
physical carcinogens that are extensively studied.

Antigen (Cont..)
28
▰ In contrast, the TSTA of virus induced tumours is virus specific; all
tumours produced by one virus would possess the same antigen.
▰ Example: nasopharyngeal carcinoma and several types of lymphoma
caused by Epstein Barr virus .

Tumour-associated Transplantation
Antigens
29
▰ Not unique to tumour cells and may also be expressed by normal cells .
▰ Their level gets exponentially high in tumour cells.

Tumour-associated Transplantation
Antigens (Cont..)
30
▰ Oncofetal antigens- proteins that are expressed on normal cells during
fetal life but not expressed in the adult normally.
 Reactivation of the embryonic genes that encode these proteins in
tumour cells results in their expression on the fully differentiated
tumour cells.
▰ Examples include alpha-fetoprotein (AFP) and carcinoembryonic antigen
(CEA).
▰ Non-oncofetal TACAs: Examples include Carbohydrate antigens (CA
125, CA 19-9), prostate specific antigen (PSA).

TATAs used as tumor markers for
diagnosis of cancers
31
Tumor markers Tumor types
Oncofetal proteins
Alpha-fetoprotein (AFP) Hepatoma, Testicular cancer
Carcinoembryonic
antigen (CEA)
Gastrointestinal cancers, Lung, ovarian
cancers
Secreted tumor antigens
CA 125 Ovarian cancers; Other epithelial
cancers
CA 19-9 Various carcinomas
Prostate-specific antigen Prostate cancer
β 2 microglobulin Multiple myeloma
Hormones
β subunit of chorionic
gonadotropin
Hydatidiform mole Choriocarcinoma;
Testicular cancers

IMMUNE RESPONSE AGAINST
TUMOUR CELLS
32
▰ Both humoral and cell-mediated immune responses are induced by tumour
antigens that result in the destruction of the tumour cells.
▰ Cell-mediated response appears to play the major role:
 Cytotoxic T cell
 NK cell.

Cytotoxic T Cells
33
▰ Number of tumours have been shown to induce tumor-specific TC cells that
recognize tumour antigens presented by class I MHC on the tumour cells.
▰ Sensitized T-cells attack the foreign tumour cells and tend to limit its
growth.
▰ T-cell subsets, cytotoxic T (Tc) cells play a significant role in tumour
killing by means of lymphokines that they release.

Natural Killer (NK) Cells
34
▰ Recognition of tumour cells by NK cells is not MHC restricted.
▰ NK cells can also kill the tumour cells without antibody.
▰ Direct lysis of tumour cells, NK cells also participate in antibody
dependent cytotoxicity (ADCC).
▰ NK cells provide first line of defence against many tumours.

CANCER IMMUNOTHERAPY
35
▰ Is the use of the immune system to treat cancer.
▰ Three main groups of immunotherapy are used to treat cancers:
 Checkpoint inhibitors
 Chimeric antigen receptor (CAR) T-cell therapy
 Antibody therapy
 Cytokines therapy
 Immunomodulators : boost up the immune system to treat cancer.

Checkpoint inhibitors
36
▰ These drugs work by blocking checkpoint proteins from binding with their
partner proteins. This will prevent the “off ” signal from being sent and
thus allows the T-cell to kill cancer cells.
▰ Example: Ipilimumab which acts against a checkpoint proteins called
CTLA-4 (cytotoxic T-lymphocyte- associated antigen 4)

Chimeric antigen receptor (CAR) T-
cell therapy
37
▰ It is a new form of immunotherapy.
▰ T-cells taken from patient’s blood are mixed with a special virus which
makes the T-cells learn how to attach to tumour cells. This is done by
inserting a gene for a special receptor called a chimeric antigen receptor
(CAR) into the T-cells. These modified T-cells are called CAR-T cells.
▰ These CAR-T cells are given to the patient, they attach to tumour cells and
kill the cancer.
▰ Example; Tisagenlecleucel for acute lymphoblastic leukemia (ALL)
▰ Axicabtageneciloleucel for large B cell lymphoma.

Monoclonal Antibodies
38
▰ Monoclonal antibody (mAb) therapies - currently the most successful form
of immunotherapy.
▰ Many mAbs are approved for treatments of a wide range of cancers

Monoclonal antibodies approved for
treatment of cancers
39
Monoclonal
antibodies
Target Approved for treatment
of cancers
Alemtuzumab CD52 Chronic lymphocytic
leukemia (CLL)
Bevacizumab Vascular endothelia
growth factor
Colorectal, lung and
renal cancer
Cetuximab Epidermal growth
factor receptor
Colorectal, the head
and neck cancer
Ipilimumab CTLA4 Metastatic melanoma
Rituximab CD20 CLL
Non-Hodgkin
lymphoma
Tositumomab CD20
Trastuzumab ErbB2 Breast cancer

Cytokine Therapies
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▰ Regulate and coordinate the behavior of the immune system. Examples
include:
 Interferon-α is used in the treatment of hairy-cell leukaemia, AIDS-
related Kaposi's sarcoma, follicular lymphoma, chronic myeloid
leukemia and malignant melanoma.
 Interleukin-2 is used in the treatment of malignant melanoma and
renal cell carcinoma.

Cancer Vaccine
41
▰ Preventive cancer vaccines:
 Example - HPV and hepatitis B vaccine
 Prevent the emergence cervical and liver cancers respectively.
▰ Therapeutic cancer vaccines:
 Treat existing cancers.
 Research is ongoing - for preparation of such vaccines.
 Vaccines against some oncogenic viruses have proven extremely
effective.

Oncolytic viruses
42
▰ Oncolytic viruses are modified in a laboratory to infect and kill certain
tumour cells. These virus are selectively replicate in cancer cells to destroy
them.
▰ Example: Talimogene laherparepvec (T-VEC) is used to treat melanoma.

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