Transplantation Immunity. Antitumor Immunity. Autoimmune Diseases

Topic of the lecture:
"Bases of transplantation immunity.
Antitumor immunity.
Aspects of autoimmune diseases."

Plan of the lecture
1. History of transplantation.
2. Selection before transplantation.
3. Graft rejection and therapy.
4. Antitumor immunity.
5. Immunotherapy of tumors.
6. Autoimmune diseases.
7. Therapy of autoimmune diseases.
© V. Kaminskyy, 2013

Definition
Transplantation – a surgical transferring of tissues
or organs from one organism (a donor) to the second
organism (a recipient).

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YuriyYuriy VoronoyVoronoy
(1895-1961)
In 1933 in Kherson first in the world
he transplanted a human kidney.

Peter MedawarPeter Medawar
(1915-1987)
British biologist.
He opened the process
of immune tolerance.
Nobel Prize in 1960
History of transplantation

Thomas StarzlThomas Starzl
(born 1926)
American surgeon-
transplantologist.
He made the first transplantion
of a human liver in 1963.

Christiaan BarnardChristiaan Barnard
(1922-2001)
Transplant surgeon.
He performed
the first transplantation
of a human heart in 1967.

Paolo MaPaolo Macchcchiariniiarini
The pioneer of regenerative surgery.
In 2008 he performed the first
transplantation of human organ with
using stem cells.
In 2011 – transplantation of organ,
a fully grown in laboratory.

Types of grafts
Autograft – donor and recipient are one and the same
person.
Isograft – donor and recipient are identical twins.
Allograft – donor and recipient belong to the same species
(from one human to another human).
Xenograft – donor and recipient
belong to different species (from animal
to human).

Transplantation
Autografts and isografts are taking root.
Allografts and xenografts are rejecting.
Continuation of graft function:
1) selection before transplantation;
2) immunosuppression after transplantation .
Selection – a choice of the most
similar in terms of antigens a pair "donor-
recipient".

Stages of selection
A. Estimation of donor-recipient compatibility:
1. Compatibility of blood groups with system AB0 and Rh factor.
2. HLA-typing.
3. Cross-match reaction.
4. Mixed lymphocyte reaction.
B. Determination of the recipient immune status (eg, presence of autoAB
in autoimmune diseases causes graft rejection even with the
compatibility of donor and recipient).
C. Determination of absolute and relative
contraindications to transplantation (multiple
organ failure, incurable oncological diseases,
active infectious processes).

Compatibility of blood groups

Histocompatibility antigens
Histocompatibility antigens (transplantation antigens) –
proteins on the cell surface that is responsible for tissue
compatibility.
The most important:
1) antigens HLA (Human Leukocyte Antigens), which are
products of genes of major histocompatibility complex;
2) erythrocytic antigens (for system AB0
and Rh factor).

The main antigens HLA
Among all these antigens the major transplantation
antigens are considered HLA-A, HLA-B and HLA-DR. Because
they are the most important structures that are recognized by the
immune system of the host during allograft rejection.
At each locus there are a large
number of alleles (variants). So will be
synthesized the certain serological types
of molecules HLA.

Matching of antigens HLA
Everyone is having 6 major antigens: three – from his father and
three – from mother.
For transplantation requires matching at least five of six major
antigens HLA.
Mismatch of two antigens does not preclude the possibility of
transplantation in principle, but greatly increases the probability of graft
rejection.
Mismatch of three or more
antigens eliminates the possibility of
transplantation from the donor to this
recipient.

HLA typing
There are two methods of authentication:
1) Sera typing1) Sera typing – identification of specific class I and class II
HLA molecules using sera typing;
- less time-consuming method, however, also less accurate.
2) DNA typing2) DNA typing – human DNA
testing by PCR;
- more time-consuming method,
however, also highly accurate.

Estimation of donor-recipient
compatibility
Cross-match reaction. Preexisting antibodies detection test
(donor’s serum is mixed with recipient’s lymphocytes → if
preexisting cytolytic antibodies are present in serum then the lysis of
donor’s leukocytes occurs and transplantation is not performed).
Mixed lymphocyte reaction. T cells
from donor are cultured with leukocytes
of recipient → the magnitude of this
response is proportional to the extent of
the MHC differences between these
individuals.

Types of rejections
1. Hyperacute rejection.
2. Acute rejection.
3. Chronic rejection.

Hyperacute rejection

Acute rejection

Chronic rejection

Monitoring
after transplantation
The most efficient prediction criteria –
immunoregulatory index (TH/ Tc).
Normally IRI = 1.5-3.0.
At IRI < 1.0 the risk of infectious complications
increases.
At IRI > 4.0 there is a risk of graft rejection.

Therapy
after transplantation
1. Permanent immunosuppression (lack of
suppression leads to risk of rejection, excessive
suppression – the development of uncontrolled infectious
complications and malignancies).
2. Prevention and treatment of
rejection crises (increasing doses of
immunodepressants, eg, pulse-therapy).
3. Prevention and treatment of
infectious processes (on a background of
immunosuppression, long courses of
antibiotics).

Immunosuppressive therapy
- corticosteroids
- azathioprine
- selective immunosuppressants (cyclosporine A, tacrolimus,
sirolimus, mykophenolate mofetil)
- antilymphocytic drugs (serum, immuno-
globulins)
- monoclonal antibodies (infliximab
(anti-TNF-α), daclizumab (anti-IL-2),
muromonab (anti-CD3))

Oncogenesis
Normally every cell is capable of a number of
divisions and then activates gene of apoptosis and
genetically programmed cell death occurs.
Atypical cells are able to block
apoptosis, that is a key factor of
oncogenesis.

Factors of tumor and
body interaction
There are four groups of factors that are involved in
tumor development:
1. Antyblastic.
2. Immune resistance of tumor.
3. Problastic that suppress the immune system.
4. Problastic that increase tumor growth.

Antyblastic factors
I. Cellular:
1) cytotoxic T-lymphocytes;
2) natural killers (NK-cells);
3) macrophages.
II. Humoral:
1) specific antibodies;
2) IL-1;
3) IL-2;
4) TNF (tumor necrosis factor);
5) interferons.

T-cytotoxic
lymphocytes
Natural
killers
MacrophagesHumoral
factors
Antyblastic factors

Factors of tumor
immune resistance
Factors that help for tumors to avoid immune surveillance:
1. Weak immunogenicity of tumor antigens.
2. Permanent modification of antigens.
3. Selection of immunologically resistant atypical cells.
4. Loss of HLA antigens from the surface of atypical cells.
5. Rapid tumor growth often outpacing the immune response.
6. Expression of receptors on atypical cells for growth factors.
7. Excessive activation of regulatory T lymphocytes.

Problastic factors that suppress
the immune system
1. Immunosuppressive agents (IL-10, PgE2).
2. Blocking antibodies.
3. CIC (circulating immune complexes).
4. TGF-β (transforming growth factor-beta).

Problastic factors that
increase tumor growth
1. Factor of tumor growth.
2. IL-2.
3. IL-6.
4. γ-IFN.
5. Dysfunction of cytotoxic T-cells.

Immunodiagnosis of tumors
I. Evaluation of the patient immune status
(immunodeficiency occurs before clinical symptoms,
immunosuppression is not total).
II. Detection of specific tumor antigens:
1) embryonic antigens;
2) tissue specyfic antigens,
associated with tumors.

Embrionic antigens
They are characteristic to the embryos and for
tumors in adults. They are not specific.
- Alpha-fetoprotein – liver cancer, testicular and prostate
tumors
- Carcinoembryonic antigen – cancer of the colon, pancreas
- Human chorionic gonadotropin – tumors
of uterus, ovaries, testes,

Tissue specyfic antigens,
associated with tumors
- Prostate specific antigen (PSA) – prostate cancer
- P-53 – bladder cancer
- CA-19-9 – pancreas cancer
- CA-125 – ovarian cancer

Methods of treating tumors
 Surgery
 Chemotherapy
 Radiotherapy
 Immunotherapy

Immunotherapy of tumors
 Monoclonal antibodies
 Infiltrative tumor cells
 Immunostimulatory factors
 Anticancer vaccines

Monoclonal antibodies
1) Monoclonal AB:
- Rituximab (for treating lymphoma);
- Herceptin (for treating lung cancer, lymphoma);
- Cetuximab (for treating colorectal cancer);
2) Monoclonal AB + toxin (cytotoxic drug):
- Milotarh (for treating leukemia);
- CAT-3888 (for treating leukemia);
3) monoclonal AB + radioisotope:
- Zevalin (for treating lymphoma);
- Bexxar (for treating lymphoma).

Infiltrative tumor cells
Lymphocytes of patient are cultured in vitro in the
presence of his atypical cells and IL-2 (growth factor).
These cells are called LAK cells (lymphokin-activated killer
cells). After that LAK cells are administered to the patient,
where they attack the tumor.

Lymphokines-activated killerLymphokines-activated killer

Before treatment After treatment
Treatment of melanoma
by LAK cells + IL-2

Immunostimulatory factors
• BCG (Bacillus Calmette-Guérin) – weakened live cow tubercle
bacillus. S/c administered in breast cancer, melanoma.
• Xenogeneic graft (skin) – it is stimulating cellular mechanisms
during rejection (in melanoma).
• Interferon-γ – the expression of HLA-I class of atypical cells
increases, making them susceptible to CD8+-lymphocytes.

Cancer vaccines
1. Patient-specific vaccines.
Vaccines are produced with tumor antigens of
individual patient.
2. Tumor-specific vaccines.
Vaccines massively synthesized for use by any
person against a particular tumor (eg, cervarix – to prevent
cervical cancer).

Autoimmune diseases
This are pathological processes which characterized by
development of an immune response against its own organs and
tissues as a result of failure autotolerance.
The most important etiological factors:
1) genetic predisposition to a breach autotolerance;
2) immunodeficiency disorders;
3) chronic infection.
Triggers: insolation, intoxication,
irradiation, stress, hypothermia, and others.
Much more common in women than in
men. The biggest risk – at the age of 20-40 years.

Division and characterization
Autoimmune diseases are divided into two groups:
1. System (SLE, RA et al.).
2. Organospecific (type I DM, myasthenia gravis, atrophic
gastritis, etc.).
Autoimmune process can be mediated both by humoral
(autoAB, CIC) and cellular (CD8+) mechanisms.
Most autoimmune diseases are
associated with antigen HLA-DR.

Immunological features of
autoimmune diseases
 Elevated blood level of gamma-globulins
 The presence of autoantibodies
 Reduced total complement in serum
 High concentrations of CIC
 Reducing activity of regulatory T cells
 Detection of damage in tissue biopsy and fixed immune
complexes

Immunohistochemistry
in glomerulonephritis

Types of autoantibodies
1. Nonspecific (universal) – are characteristic for many autoimmune
diseases (antinuclear, antimitochondrial, antiphospholipid).
2. Tissue specyfic – their influence is limited to a specific type of tissue
(AB to acetylcholine receptors in myasthenia gravis).
3. Organospecyfic – their effect is limited to the organ (AB to biliary
epithelium in primary biliary cirrhosis).

Myasthenia gravis

Graves’
disease

DM type I

Treatment
1. Immunosuppression:
a) drug (corticosteroids, cytotoxic agents);
b) surgical (thymectomy in myasthenia gravis).
2. Detoxication therapy (hemosorption,
plasmapheresis, immunosorption).
2. Intravenous immunoglobulins.
3. Stimulation of the tolerance development (eg, miloral in DM).
5. T-cell vaccination (there is aggression against autoreactive
lymphocytes).
6. Biological therapy (monoclonal AB to cytokines, its receptors,
adhesion molecules).

Cytokine
receptor
Proinflammatory
cytokine
Proinflammatory
signals
Soluble
receptor
Monoclonal
antibody
The signal is absent
Receptor
antagonist
Monoclonal
antibody
The signal is absent
Anti-inflammatory
cytokines
Inhibition of
proinflammatory cytokines

Promising methods
I. NanotNanothherapy.erapy.
II. DNA therapy.DNA therapy.
III. MMicroRNAicroRNA-therapy.-therapy.

Transplantation Immunity. Antitumor Immunity. Autoimmune Diseases

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