Transcript Transplantological immunology. Immunology of reproduction

Transplantological immunology.
Immunology of reproduction.
Congenital and acquired
immunodeficiency and secondary
immune insufficiency. .
Definition

Transplantation immunology - sequence
of events that occurs after an allograft or
xenograft is removed from donor and
then transplanted into a recipient.

A major limitation to the success of
transplantation is the immune response of
the recipient to the donor tissue.
Graft or
Transplant:
Transfer of living
cells, tissues
and organs from
one part of the
body to another
or from one
individual to
another.
History

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In 1902 A. Carrel performed the first animal kidney
transplantation, and in 1905 - a heart transplantation;
and developed vascular suture
In 1933 Yu.Voronoy world's first carried out cadaveric
kidney transplantation the patient, who suffered AKI
Laurel (USA, 1950) and Charles Dubost (France,
1951) successfully transplanted cadaveric kidneys. The
effect of the operation was short-lived, as it was not
effective suppressive therapy
In 1957 G. Dausset described the first
hystocompatibility antigen
History
In 1965 B. Petrovsky performed the first kidney
transplantation from living donor
 In 1967 Christian Barnard (South Africa)
performed the first successful human heart
transplant. After heart transplantation patient has
lived for 17 days, but he died of pneumonia and of
rejection reactions. A month later another patient
was operated on; this patient had lived for two
years after surgery

Methods of Transplantation
May take place between:
 different parts of the same
organism (autografting)
 different organisms of the
same species (allografting)
 different species
(xenografting)
genetically identical
individuals (isografting)
Autotransplantation is the transplantation of
organs , tissues or even proteins from one part of
the body to another in the same individual. Tissue
transplanted by such "autologous" procedure is
referred to as an autograft or autotransplant
•
Use: synthetic implantation
skin grafts
 bone marrow
transplantation
 hair

Acceptance of an autograft is completed
within 12 to 14 days. [© 2013 W. H. Freeman and Company.]
Isograft is tissue transferred between genetically
identical individuals. This occurs in inbred strains
of mice or identical human twins, when the
donor and recipient are syngeneic. Autograts and
isografts are usually accepted, owing to the
genetic identity between donor and recipient
Allograft is tissue transferred
between genetically different members
of the same species. In mice this means
transferring tissue from one strain to
another, and in humans this occurs in
transplants in which the donor and
recipient are not genetically identical
(the majority of cases). The transplant
is called an allograft, allogeneic
transplant, or homograft. Most human
tissue and organ transplants are
allografts
Xenograft is tissue transferred between different species (e.g.,
the graft of a baboon heart into a human). Because of significant
shortages of donated organs, raising animals for the specific
purpose of serving as organ donors for humans is under serious
consideration.
Specificity and Memory in Allograft Rejection
(b) First-set rejection of an
allograft begins 7 to 10 days
after grafting, with full
rejection occurring by 10 to
14 days.
(c) Second-set rejection of
an allograft begins within 3
to 4 days, with full rejection
by 5 to 6 days. The cellular
infiltrate that invades an
allograft (b, c) contains
lymphocytes, phagocytes,
and other inflammatory
cells. [© 2013 W. H.
Freeman and Company.]
Role of T Cells in Graft Rejection
The role of CD4+ and CD8+ T cells in allograft rejection is
demonstrated by the curves showing survival times of skin grafts
between mice mismatched at the MHC.
MAJOR HISTOCOMPATIBILITY
COMPLEX (MHC )
Schematic diagrams of class I and class II MHC molecules showing the external domains, transmembrane segments,
and cytoplasmic tails. The peptide-binding groove is formed by the membrane-distal domains in both class I and class
II molecules (blue). The membrane-proximal domains (green and red) possess the basic immunoglobulin-fold
structure; thus, both class I and class II MHC molecules are classified as members of the immunoglobulin
superfamily.
Map of Human MHC
Transplantation antigens
Major Histocompatibility Complex (MHC):
◦ Class I antigens: constitutively expressed on
surface of most cells
◦ Class II antigens: expressed on cells of
lymphoid system
◦ Expression of MHC molecules can be
upregulated by ischemia, etc.
◦ nomenclature
 HLA (human) class I: A, B, C; class II: DR, DQ
 H-2 (mouse) class I: K, D, L; class II: IA, IE
Antigenic Profiles and
Transplantation Tolerance
Tissues that share sufficient antigenic similarity, allowing transfer
without immunologic rejection, are said to be histocompatible. This is
the case when the transfer occurs between identical twins.
Tissues that display significant antigenic differences are
histoincompatible and typically induce an immune response that leads
to tissue rejection.
Antigens that determine histocompatible encoded in more than 40
different loci
The loci responsible for the most vigorous allograft rejection reactions
are located within the major histocompatibility complex (MHC ).
Because the genes in the MHC locus are closely linked, they are usually
inherited as a complete set from each parent, called a haplotype.
Minor histocompatibility locus
Minor histocompatibility antigens are recognized
only when peptide fragments are presented in
the context of self-MHC molecules
 Rejection based on only minor histocompatibility
differences is usually less vigorous but can still
lead to graft rejection

‘isohemagglutinins’
ABO compatibility between
donor and recipient is crucial to
avoid rapid graft rejection
© 2007 New Science Press Ltd new-science-press.com
Selection of the
donor
To pick up a donor is fully compatible with the
recipient to antigens HLA, very difficult, because
the number of combinations, composed of more
than 100 antigens in this family is extremely large
 Chance to find fully compatible donor is from
1:1000 to 1:1 000 000
 Probability of selection of fully compatible donor
among siblings is 1:4, whereas HLA genes are
inherited as Mendelian laws

Selection of the
donor
Find a donor is fully compatible with the
recipient for antigens HLA, among people who
are not his relatives, almost impossible, that is
why donors often pick among siblings of the
recipient
 Mean time to graft rejection in
transplantation of fully compatible for HLA
antigens relative is 22.4 year, and the
transplantation of cadaveric organ - 4.6
years

Assessment of compatibility of
donor and recipient for HLA
antigens
To assess the compatibility of the recipient of the alleged
donor :
 determine HLA antigens of the recipient,
 exclude sensitization recipient antigens HLA,
 test conducted on individual compatibility.
Also, pick up a donor matching with recipient
antigens by AB0 system. This is particularly important
in kidney transplantation.
Determination of recipient’s
HLA antigens
1. Serological methods. The main serological typing
method antigens HLA - lymphocytes toxic test
2. Molecular genetic methods
 Analysis of restriction fragment length polymorphism.
 Determination of specific oligonucleotide sequences
 PCR
3. Cell methods.
 Mixed lymphocyte culture
 The reaction cell cytotoxicity
Detection of sensitization
recipient to HLA antigen
Antibodies
to HLA antigens appear after
exposure of cells of the immune system of
the recipient of these antigens, such as
during pregnancy
The presence in the serum of the recipient
(child) antibodies to HLA antigens of the
donor (mother) is a contraindication to
organ transplantation obtained from this
donor.
Detection of sensitization recipient to
HLA antigen
Using serological methods in the serum of
the recipient can detect these antibodies:
Antibodies to antigens HLA class I:
HLA-A, HLA-B and HLA-C
Antibodies to antigens HLA class II:
HLA-DR, HLA-DQ і HLA-DP
The test of the individual
compatibility
The final stage of the selection of the donor the samples of individual compatibility
In the basis of test of individual compatibility
is lymphocyte-toxic test. To this was added
to the lymphocyte donor serum recipient
The aim - to detect any antibodies that may
react with HLA antigens of the donor and
cause transplant hyperacute rejection
Mixed Lymphocyte Reaction:
Recipient
Donor
+
(Irradiate)
Cell Proliferation
 Strong Proliferation--->High incompatibility
 Weak proliferation--->Low incompatibility
 No proliferation---> 100% compatibility
 Helps to identify any antigenic differences between
donor and recipient
Immunological
investigations after
transplantation
1.
2.
3.
Posttransplant monitoring:
Diagnosis of rejection reactions.
Monitoring the adequacy and effectiveness
of immunosuppression.
Diagnosis of infectious complications.
Immunological investigations after
transplantation
Diagnosis of graft rejection is performed
routinely in all patients after transplantation.
The only reliable method for diagnosing
transplant rejection is his biopsy, which was
carried out at least 1 time per year.
Immunological investigations after
transplantation
Determination of the absolute
number of T cells in the blood
This is the best way to assess the effectiveness
muromonaba-CD3, antithymus and
antilymphocytic immunoglobulins
Diagnosis of graft rejection
Types of transplant graft rejection
 Antibody-mediated
rejection (AMR)
Hyperacute rejection
Acute or delayed AMR
 Cellular
rejection
 ‘Chronic’ rejection
Pathogenesis of hyperacute rejection
From Silver et al.
Hyperacute rejection of cardiac xenografts
Pig to baboon; 30 min.
Guinea pig to rat; 5 min.
Courtesy of Dr. Jeff Platt, Transplantation Biology, Mayo Clinic
Types of transplant graft rejection
‘Chronic rejection’:
 Poorly defined term indicating chronic
deterioration within graft
 Occurs in some form in all organ allografts
◦
◦
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◦
Kidney: chronic allograft nephropathy
Heart: graft coronary artery disease
Lung: bronchiolitis obliterans syndrome
Liver: vanishing bile duct syndrome
May (or may not) be associated with recurrent
cellular rejection episodes
 Alloantibody may (or may not) play a role
 Not prevented with current immunosuppressive
drug therapies
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The mechanism of graft rejection
1) T T cell response to antigens of the transplant is
performed by one of two ways:
cells recognize antigens of the recipient graft directly
onto the surface of donor cells exhibiting stimulatory
activity (Direct presentation);
2) T cells recognize antigens transplant recipient
indirectly, i.e. processing after their presentation by antigen
presenting cells and the host (Indirect presentation , or - representation).
Direct path of antigen involves CD4 + and CD8 + T
cells specific for the MHC Class II molecules, and Class I
respectively. Such T cells directly recognize MHC
molecules on APC donor.
Immunosuppressive
drugs
Immunosuppressive therapy is conducted with all
patients before and after transplantation.
Exceptions are those cases where the donor and
recipient - identical twins.
Immunosuppressive therapy generally suppresses
all immune responses, including the response to
bacteria, fungi and even tumors.
Immunosuppressive
drugs
Current approaches to immunosuppressive
therapy involves the simultaneous use of multiple
immunosuppressive drugs and their uses before
and after transplantation to prevent and treat
graft rejection
Immunosuppressive drugs
Glucocorticosteroids: prednisone
 Small molecule drugs
◦ azathioprine
◦ calcineurin inhibitors: cyclosporine, tacrolimus
◦ target of rapamycin inhibitors: sirolimus (a.k.a rapamycin)
◦ IMPDH inhibitors: mycophenolate mofetil
◦ lymphocyte recirculation (S-1-P) inhibitors: FTY720
 Depleting antibodies
◦ rabbit polyclonal antilymphocyte globulin
◦ anti CD52 (Campath-1h), anti CD3
◦ B cell depletion: anti CD20
 Non-depleting antibodies and fusion proteins
◦ anti CD25
◦ CTLA4Ig fusion protein
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Kidney transplant
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Kidney transplant compared with transplantation of other
organs, relatively long gained considerable spread
First experimental kidney transplant performed in 1902 by A.
Carrel. Jeboulay in 1906 transplanted pig kidney into the hands of
a patient who suffered from uremia.
In 1933, JJ Voroniy, the world's first cadaveric kidney transplants
carried out to girl who suffered acute renal failure, which
developed as a result of poisoning by mercuric chloride.
Unfortunately, the patient died two days after surgery.
Heart transplant
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The first successful human heart transplant performed in
1967, K. Bernard (South Africa). Patients after heart
transplantation has lived for 17 days, but he died of
pneumonia and of rejection reactions. A month later, K.
Bernard operated on another patient, who had lived for two
years after surgery.
The first successful heart transplant operation performed in
Russia by Shumakov in 1987 at the Moscow Research
Institute of transplantation of organs and tissues.
Over the last 7-8 years, performed more than 13,000 heart
transplants.
Lung transplant
For the first time in an experiment performed
lung transplantation Demikhov in Moscow in
1949 and Metras in France in 1950
 The clinic Hardy in the U.S. performed lung
transplantation in 1963, the patient died 18 days
after surgery.
 The first successful lung transplantation with
long-term survival Cooper held in 1983 in
Toronto.
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Liver transplant
By 2006, the world has accumulated experience
of more than 50 000 transplants of the liver.
 First orthotopic liver transplantation was
performed in 1963 p. by Starzl (USA), and
heterotopic - 1964 p. Absolonom (USA).
Unfortunately, the patients died.
 Only in 1968, p. T. Starzl reported the first patient
who survived.
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Indications for bone marrow transplantation
Diseases
Alotransplantation Avtotransplantation
Malignant tumors
Acute leukemias
+
+
Chronic myeloid leukemia
+
+
Myelodysplastic syndromes
+
—
Lymphomas
+
+
Lymphogranulomatosis
+
+
multiple myeloma
+
+
Chronic Lymphocytic Leukemia
+
+
Breast Cancer
—
+
Malignant tumors of the testis
—
+
Ovarian cancer
—
+
Neuroblastoma
+
+
Peripheral primitive neuroectodermal tumor
—
+
Nefroblastoma (Wilms tumor)
—
+
Ewing's sarcoma
—
+
Tissue Transplant Technology
(implantation cell cultures)
 The
method of functional recovery of the
affected organ transplantation and tissue
culture cells - the so-called method of cell
transplantation therapy («cell
transplantation therapy»).
 The prototype of all research in this area is
the transfusion of blood and its
components.
Tissue Transplant Technology
(implantation cell cultures)
Implantation of autologous cultured epithelium used in the
treatment of thermal lesions, allowing you to achieve previously
unattainable clinical outcomes.
 Its experience in artificial insemination using culture techniques.
 Successfully used cadaveric corneal transplantation in the treatment
of eye injuries and degenerative disorders.
 In experiments in the treatment of diabetes used
alotransplantation cell cultures of pancreas.
 The methods of restoration of damaged myocardium by means of
replanting satellite cells of skeletal muscle in the myocardium.

Immunology of
Reproduction
Actuality
Study the functioning of reproductive
organism of immune professionals attract
new technological possibilities for
detecting immunological causes
miscarriage, male and female infertility.
Immunology of
Reproduction
The immune system provides special protection of male
and female reproductive systems that ensure procreation (the transfer of
genetic information to future generations)

It is important that the male reproductive system
functions like bone marrow, is constantly regenerating a large number of
cells, providing active spermatogenesis
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Female reproductive system also provides oocyte
differentiation, but in the process of ovulation is not observed
phenomenon of "excess" female sex cells

For fertilization woman's body should not destroy
immunologically antigenically foreign male gametes, and create favorable
conditions

Features of
immunosuppression during
normal pregnancy
 Protein
early phase of pregnancy.
 Antigen TLX.
 Lack of trophoblast classical histocompatibility antigens
class I.
 Availability trophoblast antigens HLA locus G, causing a
lack of trophoblast-specific T-killer cells, enhances the
maturation of T-suppressor cells, contributes to
suppression of EC cells, suppression of macrophage
function
 Barrier function of the placenta.
Features of
immunosuppression during
normal pregnancy
The placenta acts as a sorbent anti-HLA-antibodies.
Immunoregulatory role of the placenta is in the production of
human chorionic gonadotropin, placental lactogen, trophoblastic beta
1-glycoprotein, progesterone-induced suppressive factor suppression
of EC-cell production of TNF-alpha, strengthening of T-helper type 2,
the formulation of glucocorticoids, transforming growth factor
beta1, prostaglandin E2, alpha 2-fetoprotein
Enhancement of T-helper type 2 diabetes leads to increased
production of interleukins 4, 10, no cytotoxic Ig G1
Decrease of T-helper type 1 results in decreased production of
interleukin 2, interferon-gamma, TNF-alpha production of cytotoxic
Ig G2a
Rhesus-conflict
Rhesus-conflict
underlying hemolytic disease of the
newborn, is an example of immunopathology of
pregnancy.
The basis of this conflict is the presence of fetal Rh (D)
antigen and the absence of it in mother. Incomplete IgGantibodies produced while in the mother can pass
through the placenta and cause destruction of red blood
cells of the fetus.
Methods of detecting IgG-antibodies antirhesus is
indirect Coombs test.
Immunology of spontaneous
Abortion (miscarriage)
Often at the heart of spontaneous abortions based on the
following immune mechanisms:
poor recognition of HLA-antigens and insufficient production
of blocking antibodies;
production of cytokines or soluble immune factors that show
the damaging effects on the fetus or placenta;
production of autoantibodies to phospholipids that function
as adhesion molecules and are required for cell fusion during
formation of syncitiotrophoblast;
production of antibodies that bind blocking antibodies.
activation of T-helper type 1 in the mother, resulting in an
inadequate immune response to embryo
Immunology of infertility
Marriage is considered infertile if he remains childless after 2
years of sexual activity without contraceptives.
 According to WHO, there are more 8-9% of infertile families, in
terms of absolute numbers - is tens of millions of cases. In Eastern
Europe today 10-15% of marriages are considered infertile.

Fertility marriage almost equally dependent on the reproductive
capacity of husband and wife, though more often it turns infertility
in women (60-65% of infertile marriages).
 Prominent among the causes of infertility occupied by the
inflammation of the genitals (over 75%) - with a clear
immunological component.

Features of immune mechanisms in
immunodependent forms of infertility
in women :
Increased production of interferon-gamma, which leads to increased
function of EC cells, LAK cells, inhibition of secretion of granulocytemacrophage colony-stimulating factor (GM-KSCH) epithelial cells of the
uterus, direct damage to the cells of the trophoblast.
 Increased production of TNF-alpha contributes to inhibition of
proliferation and differentiation of trophoblast cells, induction of
trophoblast cell death due to apoptosis.
 Simultaneous enhancement products IFN-alpha, TNF-alpha and IL-2
leads to abortion.
 Reduced production of IL-4, 10.
 Improved compatibility for marriage HLA-antigens.
 Secondary immunodeficiency.
 Auto (immune) conflict.

The main conditions that promote the formation
of the male antisperm antibodies :
 Injuries
to the testicles, scrotum, varicocele (varicose
veins surrounding the spermatic cord).
 Cryptorchidism.
 Infections (chlamydia, mycoplasma, herpes and papilloma
viruses).
 Oncopathology
 Blockage vas ways.
 Operations on the abdomen.
 Severe purulent infection of the abdominal cavity, which
can occur in the spermatic cord injury.
 Vibration
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