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Transplantation Immunity

Transplantation can be defined as the transfer of cells, tissues, or organs from one site in an
individual to another, or between two individuals. In the latter case, the individual who
provides the transplant organ is termed a donor and the individual
receiving the transplant is known as the recipient. (Parija)

There are four (4) types of transplants: Autograft, syngraft, allograft and xenograft. An
autograft is the transfer of an individuals own tissue or organ from one site to another in
the body. Hence, the recipient acts as both the donor and the recipient.
While, a syngraft is the transfer of tissue between identical twins, an allograft is the
transfer of tissue or an organ between genetically different members of the same species.
However, a xenograft is the transfer of tissues or organs between members of different
species.

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Rejection is most often seen in allograft and xenograft transfers. The adaptive immunity
response is responsible for rejection. Here, the receiving individuals immune system
rejects the tissue being transplanted, commonly known as graft rejection. MHC molecules
are responsible for almost all rejection reactions. The major histocompatibility genes
include class I and class II MHC genes. These genes, which are located on the short arm of
chromosome 6 in humans, encode antigens that should match if a tissue or organ graft will
survive in the recipient and are located in the MHC region. These histocompatibility
antigens are expressed on cell surfaces that are encoded by the minor histocompatibility
loci, not the major histocompatibility locus. Although their response is weaker than the
major histocompatibility antigens, they are multiple and their joint effect will still aid in
organ or tissue graft rejection. T helper cells and T cytotoxic cells are both responsible for
mediating these reactions. Class 11 Major histocompatibility complex functions as a
sensitizer for the recipients immune system, which in turn activates the alloreactive helper
T cell leading to clonal expansion.

There are two (2) presentation types for the recognition of the allogeneic MHC:
Direct and indirect presentation. Direct presentation has to do with the recognition of self
and non-self by the immune system. It is whereby Antigen Presenting cells (APCs) present
MHC molecules that are intact. A normal T-cell receptor is used to decipher between a self-
MHC molecule and foreign peptide, with an allogeneic MHC molecule and foreign peptide.
This step is carried out because the allogeneic MHC could resemble and operate like a self-
MHC molecule with a foreign peptide. T cells high frequency reactivity to allogeneic MHC
molecules, results in impactful allograft immune responses.

Indirect presentation entails the antigen presenting cells displaying processed allogeneic
MHC molecules in comparison to direct presentation and intact MHC molecules. Recipient
APCs processes the donor MHC and displays the peptides from the allogeneic MHC
molecules. Allorecognition by both CD4+ and CD8+ T cells occur through the Class 11 MHC
molecules and class 1 MHC molecules respectively.

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(Alberto SanchezFueyo, 2010)


Pathways of alloantigen presentation.

Stages of cell mediated graft rejection are: the sensitization and effector stage. The
sensitization phase has to do with the recognition of the donor MHC molecule and the
corresponding peptide ligand, which is present in the cleft of the MHC molecule. Class 1
MHC molecules have peptides in their grooves, which come from proteins made in the
allogeneic cell. The peptides in the grooves of class 11 MHC molecules are the proteins,
which go through the endocytic pathway of the allogeneic APC, which allows protein to be
taken up, and processed. Allogeneic graft and the alloantigen, which are present on graft
cells, induce host T cell proliferation, seen in lymphocyte reactions. The CD4+ T cells
mainly recognize class 11 alloantigens directly or by the presentation of the alloantigen
peptides on the host APC.

Effector mechanisms in allograft rejection involve cell-mediated reactions and antibody -


dependent cell mediated cytotoxicity (ADCC). The most common cell mediated reactions
include delayed type hypersensitivity and cytotoxic T lymphocyte mediated cytotoxicity.
The not so common stage consists of destruction of the ADCC along with breakdown of the
antibody complement

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Complex. Infiltration of T cells, macrophages, and cytokines elicit a delayed type


hypersensitive reaction, indicative of graft rejection.

The clinical features of graft rejection include: hyperacute, acute and chronic rejections.
Hyperacute rejection occurs the earliest of all the other types of rejection listed. Within a
span of the first few hours after transplantation is completed, preformed antibodies against
ABO or MHC antigens are produced. The binding of antibodies to the transplanted tissues,
mediates the complement system with granulocytes present and inflammatory responses
or by the activation of the ADCC. Features of the hyperacute rejection are:
i. Giant platelet clumps which results in thrombosis, ischemia in different organs
and necrosis of various tissues.
ii. May result in losses of the graft tissue, but with careful cross matching, can be
avoided.
iii. Makes it harder for xenogeneic transplantation to occur (e.g., pig to human).

Acute rejection is not as rapid as the hyperacute rejection and occurs in the first few days
to weeks after transplantation would have taken place. A secondary immune response is
elicited here whereby patient would have been sensitized to the HLA antigens in the organ
donor. If graft rejection is first week after, a primary response is seen. A high percentage of
transplantation patients have single or multiple acute rejection scenes. T lymphocytes are
the main mediator in the immune response with monocytes, T lymphocytes and B-
lymphocytes, natural killer cells, neutrophils and eosinophils, all aiding in the rejection
process. The clinical presentations which diagnoses acute rejection include:
i. The grafted organ does not carry out the expected function.
ii. Surgical biopsy of the grafted organ is tested to gain confirmation.
iii. Mononuculear sell infiltration into grafted tissues is a hallmark.
iv. Cytokines in serum, for example, IL-2 and IL-4 and urine cytology tests can be
performed to diagnose this rejection type.
Immunosuppressants are key to helping with acute rejection.

Delayed or chronic rejection is due to immune and non immune processes over time.
There is an on-going loss of function of the grafted organ, which leads to vascular
endothelial injury, which is indicative of chronic rejection. There is an infiltration of
granulocytes, monocytes and platelets at the injured site. Fibrosis of the grafted organ will
be inevitable, since the endothelium is destroyed and coated by a layer of fibrin, platelets
and fibroblasts along with smooth muscle cells.

One would argue, why risk doing transplantation, if rejection rates are as high as 70%?
Prevention of graft rejection is important for patients who have successfully completed
transplantation. Immunosuppression is key to prevention, either by radiation treatment,
corticosteroids and antilymphocyte serum. T cells that are

Responsible for strong rejection of graft tissue/organs can be specifically inhibited by using
cyclosporin A and rampamycin.

A graft versus host (GVH) reaction is where a recipient of a graft organ is suffering from
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an immunodeficiency and there are immunocompetent cells present in the graft organ. This
poses a threat to the patient in developing a GVH reaction, which can occur approximately
two (2) months following transplantation.
To be considered as a GVH reaction, three important aspects to be observed are:
i. T cells must be present in the donor graft.
ii. The recipient/host must suffer from some immunodeficiency.
iii. Antigens from the recipient, such as MHC proteins, will be seen as foreign to the
donor.
Many GVH reactions results in a host of infections and ultimately, death. As T cells become
activated, proliferate and differentiate into CD4+ and CD8+ cells, the GVH reaction occurs,
because the host is immunocompromised. Treatments for the transplantation rejection as
listed earlier in this document can be used in this reaction along with Thalidomide, which
controls chronic GVH that does not respond to the common drugs. Thalidomide, however,
is a tranquilizer drug that disturbs the development of the embryo or fetus (teratogenic).

(Graft-versus-host disease , 2010)

Tumor Immunity

The presence of antigens on tumor cells and the immune response to them can be defined
as tumor immunology. Without differentiation, antigens are mostly seen in the prenatal
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period e.g. Alpha fetoprotein and carcinoembryonic antigen. Tumors are formed when
there is an imbalance of the cell death and renewal, and uncontrollable production of large
number of clones of a single cell group.

A tumor that does not invade healthy surrounding tissue and remains in its original space,
not uncontrollable with its growth, is termed as benign. While, a tumor that
characteristically grows continually and is invasive along with progressive, can be termed
as malignant. Cancer specifically surrounds this area of malignant tumors. A malignant
tumor displays metastasis that spreads and undergoes continual proliferation. Hence, a
primary tumor in one place can cause a secondary tumor at a different place.

Malignant cells have certain features, which characterize them, such as:
i. Cells malfunction and start competing with self cells for the basic space and
nutrition.
ii. Due to limited differentiation, cells lose their functionality and their malignancy,
or ability to cause disease increases.
iii. Cell division can no longer be controlled, and hence, rate increases significantly.
iv. Movements from their usual space, for e.g., invasion of the basement membrane
which houses the vasculature, causes a spread of unhealthy cells which is said to
be metastasis.

Tumor antigens have two (2) broad categories, namely: tumor specific antigens and
tumor associated transplantation antigens.
Tumor specific antigens are isolated to tumors only. MHC class 1 response is mediated
when the products of mutated genes (tumors) are presented causing a cell mediated
immune reaction. Mutation in certain genes that regulate cell growth causes malignancies.
Ras proto-oncogene in malignant cells cause amino acid substitutions (at specific locations
12,13 or 61), bind guanine nucleotides, rise in enzymatic activities of products. These
products activate cellular immune response. (Parija) The cells develop a greater ability to
transform.
When integrated with proviral genome, tumor cells are still recognized by the cellular
immune response. Some viruses include: Epstein Barr virus (EBV), hepatitis B virus
(HBV), hepatitis C virus (HCV), etc.

Tumor associated transplantation antigens (TATAs) are associated with malignant


transformations. TATAs can be type:
i. Tumor associated carbohydrate antigens
ii. Differential antigens
iii. Oncofetal antigens
The tumor associated carbohydrate antigens are detected in breast and pancreatic
cancers and consist of the abnormal form of mucin associated antigen.

Differential antigens look at CD10 and prostate specific antigens (PSA). The PSA antigen is
use to diagnose prostate cancer.

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Oncofetal antigens are found in embryonic life as embryonic and malignant cells. Alpha
fetoprotein and carcinoembryonic antigens are found in hepatomas and colonic cancers.

Prostate specific antigens are an important indicator of prostate cancer. The PSA is a
gamma seminoprotein or kallikrein like serine protease produced solely by epithelial
cells in the prostate gland.

(Government of Ontario, 2003)

Antigens of tumors that can cause a reaction of an immune response can be:
i. Antigens that are presented by tumor cells and the transformation of tumor cells
leading to production of abnormal products.
ii. Some tumor cells are only presented when specific cells are undergoing
differentiation. This activity is observed by the immune system.
iii. Overexpression of the antigens on tumor cells causes a strong immune response.
The cellular immune response is very important in tumor immunity. Antitumor responses
and activation of the non-specific immunoregulatory factors occur as a result of the antigen
recognition.
i. Upregulating is whereby the tumor killing function is activated. Important cells,
which play a major role, are: mononuclear phagocytes, NK cells and
granulocytes.
ii. ADCC is also activated.
iii. Macrophages are released and are a part of the reaction. For e.g. in tumor
regression, macrophages surrounds tumor cells. This is seen in many different
cancers.

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(Diagnostics,
2009 - 2017)

Humoral
immune
responses
and involves
B
lymphocytes
and the ADCC
against
tumor cells.
The B cells
produce
tumor-
specific
antibodies.
The
Fcgamma
receptors
mediate the
ADCC
through NK
cells,
monocytes
and granulocytes. Here, IgG coated tumor cells are destroyed.

Ehrlich presented that tumor cells are seen as foreign by the immune system, and is
eliminated as a result. Here, she has the basic concept of immunosurveillance.

Immunosurveillance as described by Burnet is whereby the immune system monitors cell


activities and attempts to destroy or cause cessation of growth of cancer cells, hence,
preventing development of malignancy.

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(Diagnostics, 2009 - 2017)

Immunotherapy of cancer can be linked to either of the following groups: antigen


nonspecific treatment or antigen specific treatment.

Antigen nonspecific treatment involves treatment with Bacillus Calmette Guerin (BCG)
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vaccine, Corynebacterium parvum and other non-specific immune modulators.


The BCG vaccine has many advantages in destroying tumors:
i. Regression of tumors, especially solid tumors.
ii. Activation of macrophages and NK cells.
iii. Has good reviews in treatment of bladder cancer, malignant melanomas, stage I
lung cancer, and certain leukemia.
The corynebacterium parvum has antitumor activities, which are beneficial to cancer
patients also.
i. Stimulation of macrophages and B cells.
ii. When used with cyclophosphamide, enhances activities.
iii. Has a great advantage when used in the treatment of metastasis breast cancer
and some lung cancers.
Other nonspecific immune modulators include:
i. Dinitrochlorobenzene squamous and basal carcinoma
ii. Levamisole mediates macrophage function and cell mediated immunity.
iii. Tuftsin to stimulate phagocytic cells.

Antigen specific treatment includes:


i. Vaccination with antigen of the tumor.
ii. Transfer factor treatment.
iii. Immune RNA treatment
iv. Monoclonal antibodies, which acts against tumor associated antigens (TAAs).
v. Use of neuraminidase helps to change the tumor antigenicity.

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References

Bibliography
Alberto SanchezFueyo, T. B. (2010, 11 9). Immunologic Basis of Graft Rejection and
Tolerance Following Transplantation of Liver or Other Solid Organs. Retrieved from NCBI:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866688/

Diagnostics, C. (2009 - 2017). Tumor immunity. Retrieved from Creative Diagnostics CD:
http://www.creative-diagnostics.com/Tumor-Immunity.html

Government of Ontario, C. (2003). Summary of the Recommendations. Retrieved 06 27,


2012, from Ministry of Health and Long term care:
http://www.health.gov.on.ca/english/providers/pub/cancer/psa/psa_summary/summary
.html

Graft-versus-host disease . (2010, 08 04). Retrieved from MedLibes online medical library:
http://medlibes.com/entry/graft-versus-host-disease

Parija, S. C. Textbook of Microbiology & Immunology (second edition ed.). New Delhi, India:
Elsevier.

Mayo Foundation for Medical Education and Research.

Works Cited
Alberto SanchezFueyo, T. B. (2010, 11 9). Immunologic Basis of Graft Rejection and
Tolerance Following Transplantation of Liver or Other Solid Organs. Retrieved from NCBI:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866688/

Diagnostics, C. (2009 - 2017). Tumor immunity. Retrieved from Creative Diagnostics CD:
http://www.creative-diagnostics.com/Tumor-Immunity.html

Government of Ontario, C. (2003). Summary of the Recommendations. Retrieved 06 27,


2012, from Ministry of Health and Long term care:
http://www.health.gov.on.ca/english/providers/pub/cancer/psa/psa_summary/summary
.html

Graft-versus-host disease . (2010, 08 04). Retrieved from MedLibes online medical library:
http://medlibes.com/entry/graft-versus-host-disease

Parija, S. C. Textbook of Microbiology & Immunology (second edition ed.). New Delhi, India:
Elsevier.

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