Transplantological immunology. Immunology of reproduction. Congenital and acquired immunodeficiency and secondary immune insufficiency.. Transplantological.

Transplantological Transplantological immunology. Immunology immunology. Immunology of reproduction. Congenital of reproduction. Congenital and acquired and acquired immunodeficiency and immunodeficiency and secondary immune secondary immune insufficiency.insufficiency. . .

DefinitionDefinitionTransplantation 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 Graft or TransplantTransplant: : Transfer of living Transfer of living cells, tissues cells, tissues and organs from and organs from one part of the one part of the body to another body to another or from one or from one individual to individual to another.another.

HistoryHistoryIn 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

HistoryHistoryIn 1965 B. Petrovsky performed the first

kidney transplantation from living donorIn 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

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)

Methods of Transplantation

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.]

IsograftIsograft is tissue transferred between is tissue transferred between genetically identical individuals. This genetically identical individuals. This occurs in inbred strains of mice or occurs in inbred strains of mice or identical human twins, when the donor identical human twins, when the donor and recipient are syngeneic. Autograts and recipient are syngeneic. Autograts and isografts are usually accepted, and isografts are usually accepted, owing to the genetic identity between owing to the genetic identity between donor and recipient donor and recipient

AllograftAllograft is tissue transferred is tissue transferred between genetically different between genetically different members of the same species. members of the same species. In mice this means transferring In mice this means transferring tissue from one strain to tissue from one strain to another, and in humans this another, and in humans this occurs in transplants in which occurs in transplants in which the donor and recipient are not the donor and recipient are not genetically identical (the genetically identical (the majority of cases). The majority of cases). The transplant is called transplant is called an allograft, allogeneic an allograft, allogeneic transplant, or homograft. Most transplant, or homograft. Most human tissue and organ human tissue and organ transplants  are allograftstransplants  are allografts

XenograftXenograft is tissue transferred between different is tissue transferred between different species (e.g., the graft of a baboon heart into a species (e.g., the graft of a baboon heart into a human). Because of significant shortages of human). Because of significant shortages of donated organs, raising animals for the specific donated organs, raising animals for the specific purpose of serving as organ donors for humans is purpose of serving as organ donors for humans is under serious consideration.under serious consideration.

(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.]

Specificity and Memory in Allograft Rejection

Role of T Cells in Graft Role of T Cells in Graft RejectionRejection

The role of CD4+ and CD8+ T cells in allograft The role of CD4+ and CD8+ T cells in allograft rejection is demonstrated by the curves showing rejection is demonstrated by the curves showing survival times of skin grafts between mice survival times of skin grafts between mice mismatched at the MHC.mismatched at the MHC.

MAJOR MAJOR HISTOCOMPATIBILITY HISTOCOMPATIBILITY COMPLEX (COMPLEX (MHCMHC ) )

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 MHCMap of Human MHC

Transplantation antigensTransplantation antigensMajor 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 Antigenic Profiles and Transplantation ToleranceTransplantation 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 lociThe 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 Minor histocompatibility locuslocus

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

© 2007 New Science Press Ltd new-science-press.com

ABO compatibility between donor and recipient is

crucial to avoid rapid graft rejection

‘isohemagglutinins’

Selection of Selection of the donorthe 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 Selection of the donorthe 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 Assessment of compatibility of donor compatibility of donor and recipient for HLA and recipient for HLA antigensantigensTo 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 Determination of recipient’s HLA recipient’s HLA antigensantigens

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 PCR3. Cell methods. Mixed lymphocyte culture The reaction cell cytotoxicity

Detection of sensitization Detection of sensitization recipient to HLA antigen 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 Detection of sensitization recipient to HLA antigen 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 The test of the individual compatibilitycompatibility

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 Mixed Lymphocyte Reaction:Reaction:

Strong Proliferation--->High incompatibility

Weak proliferation--->Low incompatibility No proliferation---> 100% compatibility Helps to identify any antigenic differences

between donor and recipient

DonorRecipient

(Irradiate) Cell Proliferation+

Immunological Immunological investigations investigations after after transplantationtransplantation

Posttransplant monitoring: 1. Diagnosis of rejection reactions. 2. Monitoring the adequacy and

effectiveness of immunosuppression. 3. Diagnosis of infectious complications.

Immunological investigations Immunological investigations after transplantationafter 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.

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

Immunological investigations Immunological investigations after transplantationafter transplantation

Diagnosis of graft Diagnosis of graft rejection rejection

Types of transplant graft rejectionTypes of transplant graft rejectionAntibody-mediated rejection (AMR)Hyperacute rejectionAcute or delayed AMR

Cellular rejection‘Chronic’ rejection

Pathogenesis of hyperacute rejectionFrom Silver et al.

Courtesy of Dr. Jeff Platt, Transplantation Biology, Mayo Clinic

Pig to baboon; 30 min. Guinea pig to rat; 5 min.

Hyperacute rejection of cardiac xenografts

Types of transplant graft rejectionTypes of transplant graft rejection

‘Chronic rejection’: Poorly defined term indicating chronic

deterioration within graftOccurs in some form in all organ allografts

◦ 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 roleNot prevented with current immunosuppressive

drug therapies

The mechanism of graft The mechanism of graft rejectionrejection1) 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 - re-presentation).

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 Immunosuppressive drugsdrugs

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 Immunosuppressive drugsdrugs

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 drugsImmunosuppressive 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

Kidney Kidney transplanttransplant

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 Heart transplanttransplantThe 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 transplantLung 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.

Liver Liver transplanttransplant

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.

Indications for bone marrow Indications for bone marrow transplantationtransplantation

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 Tissue Transplant Technology (implantation Technology (implantation cell cultures)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 Tissue Transplant Technology (implantation Technology (implantation cell cultures)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

ActualityActuality

Study the functioning of reproductive organism of immune professionals attract new technological possibilities for detecting immunological causes miscarriage, male and female infertility.

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 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

Immunology of Reproduction

Features of Features of immunosuppression immunosuppression during normal pregnancyduring 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 Features of immunosuppression immunosuppression during normal during normal pregnancypregnancyThe 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-fetoproteinEnhancement of T-helper type 2 diabetes leads to increased production of interleukins 4, 10, no cytotoxic Ig G1Decrease of T-helper type 1 results in decreased production of interleukin 2, interferon-gamma, TNF-alpha production of cytotoxic Ig G2a

Rhesus-conflictRhesus-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 IgG-antibodies 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 Immunology of spontaneous Abortion spontaneous Abortion (miscarriage)(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 Immunology of infertilityinfertility

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 Features of immune mechanisms in mechanisms in immunodependent forms of immunodependent forms of infertility in women infertility in women ::

Increased production of interferon-gamma, which leads to increased function of EC cells, LAK cells, inhibition of secretion of granulocyte-macrophage 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 The main conditions that promote the formation of the male antisperm formation of the male antisperm antibodies 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.

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