Transcript immunization

Transplantation
Transplantation
= transfer of tissue or organ
● autologous - donor = recipient
● syngeneic - genetically identical donor and recipient
(identical twins)
● allogeneic - genetically nonidentical donor of the
same species
● xenogenic - the donor of another species
● implant - artificial tissue compensation
Allotransplantation
●
differences in donor-recipient MHC gp and secondary
histocompatibility Ag
●
alloreactivity of T lymphocytes - the risk of rejection and
graft-versus-host disease
●
direct detection of alloantigens – recipient T lymphocytes
recognize the different MHC gp and non-MHC molecules
on donor cells
●
indirect recognition of alloantigens - APC absorb different
MHC gp from donor cells and present the fragments to
T lymphocytes
● CD8+ T cells recognize MHC gp I.
● CD4+ T cells recognize MHC gp II.
Testing before transplantation
● ABO compatibility
-risk of hyperacute or accelerated rejection
(= formation of Ab against A or B Ag on graft vascular
endothelium)
● HLA
typing (determining of MHC gp alelic forms)
phenotyping and genotyping by PCR
● Cross-match
- lymfocytotoxic test – detection of preformed Ab
(after blood transfusions, transplantation, repeated childbirth)
●
Mixed lymphocyte reaction - testing of T lymphocytes
alloreactivity, monitor for reactivity of lymphocytes
to allogeneic HLA
HLA typing
a) phenotyping: Evaluation of HLA molecules using typing
serums
Typing antiserums = alloantiserums of multipar (created
cytotoxic Ab against paternal HLA Ag of their children), serum
of patients after repeated blood transfusions, monoclonal Ab
- molecules HLA class I: separated T lymphocytes
- molecules HLA class II: separated B lymphocytes
b) genotyping: evaluation of specific alleles
DNA typing of HLA class II: DR, DP, DQ by PCR
Cross-match test
● determination of preformed antibodies
● recipient serum + donor lymphocytes + rabbit complement
→ if cytotoxic Ab against donor HLA Ag are present in
recipient serum (called alloantibodies = Ab activating
complement) → lysis of donor lymphocytes.
Visualization of dye penetration into lysis cells.
● positive test = the presence of preformed Ab → risk of
hyperacute rejection! → contraindication to
transplantation
Mixed lymphocyte reaction (MRL)
● determination of T lymphocytes alloreactivity
● mixed donor and recipient lymphocytes → T lymphocytes
after recognition of allogeneic MHC gp activate and proliferate
One-way MRL
● determination of recipient T lymphocytes reactivity against
donor cells
● donor cells treated with chemotherapy or irradiated lose the
ability of proliferation
Immunologically privileged sites and tissues
• Transplantation of some tissues don´t lead to the induction of
allogeneic reactivity
• minimal content of lecocytes
• mechanisms that prevent to the development of
injurious inflammation
• Evolutionarily significant, protection of vital organs (brain,
eye, gonads)
• Factors protecting immunologically privileged structures
• isolation from the immune system
• preference of TH2 reactoin, supression of TH1 reaction
• FasL expression
• production of TGFb
Rejection
Factors:
● The
genetic difference between donor and recipient,
especially in the genes coding for MHC gp (HLA)
● Type
of tissue / organ - the strongest reactions against
vascularized tissues containing many APC (skin)
● The
activity of the recipient immune system - the
immunodeficiency recipient has a smaller rejection reaction;
immunosuppressive therapy after transplantation –
suppression of rejection
● Status
of transplanted organ - the length of ischemia, the
method of preservation, traumatization of organ at collection
Hyperacute rejection
● minutes to hours after transplantation
● humoral mediated immune response
mechanism:
● if in recipients blood are present preformed or natural
Ab (IgM anti-carbohydrate Ag) before transplantation →
Ab + Ag of graft (MHC gp or endothelial Ag) → graft
damage by activated complement (lysis of cells)
● the graft endothelium: activation of coagulation factors and
platelets, formation thrombi, accumulation of neutrophil
granulocytes
prevention:
● negative cross match before transplantation, ABO
compatibility
Accelerated rejection
● 3 to 5 days after transplantation
● caused by antibodies that don´t activate complement
● cytotoxic and inflammatory responses triggered by
binding of antibodies to Fc-receptors on phagocytes and
NK cells
prevention:
● negative cross match before transplantation,
ABO compatibility
Acute rejection
● days to weeks after the transplantation or after a lack of
immunosuppressive treatment
● cell-mediated immune response
mechanism:
● reaction of recipient TH1 and TC cells against Ag of graft
tissue
● infiltration by lymphocytes, mononuclears, granulocytes
around small vessels → destruction of tissue transplant
Chronic rejection
● from 2 months after transplantation
● the most common cause of graft failure
mechanism is not fully understood:
● non-immunological factors (tissue ischemia) and TH2
responses with production alloantibodies, pathogenetic
role of cytokines and growth factors (TGF β)
● fibrosis of the internal blood vessels of the transplanted
tissue, endothelial damage →impaired perfusion of
graft → gradual loss of its function
dominating findings: vascular damage
Bone Marrow Transplantation
● Removal of hematopoietic stem cells
● Myeloablation
● Transplantation
● Engraftment
● Rejection
● Graft-versus-host reaction
Graft-versus-host (GvH) disease
● after bone marrow transplantation
● GvH also after blood transfusion to immunodeficiency
recipients
● T-lymphocytes in the graft bone marrow recognize recipient
tissue Ag as foreign (alooreactivity)
Acute GvH disease
● days to weeks after the transplantation of stem cells
● damage of liver, skin and intestinal mucosa
● prevention: appropriate donor selection, the removal
of T lymphocytes from the graft and effective
immunosuppression
Chonic GvH disease
● months to years after transplantation
● infiltration of tissues and organs by TH2 lymphocytes,
production of alloantibodies and cytokines → fibrosis
● process like autoimmune disease: vasculitis, scleroderma,
sicca-syndrome
● chronic inflammation of blood vessels, skin, internal
organs and glands, which leads to fibrosis, blood
circulation disorders and loss of function
Graft versus leukemia effect (GvL)
● donor T lymphocytes react against residual
leukemick cells of recipient (setpoint response)
● mechanism is consistent with acute GvH
● associated with a certain degree of GvH (adverse
reactions)
Immunologic relationship
between mother and allogenic
fetus
Immunologic relationship between mother and
allogenic fetus
● fetal cells have on the surface alloantigens
inherited from his father
● pregnancy = "semiallogenic transplantation“
Tolerance of fetus by mother allow the following mechanisms:
● the relative isolation of the fetus from maternal immune
system (no mixing of blood circulation)
● trophoblast - immune barrier witch protects against mother
alloreactive T lymphocytes
- don´t express classical MHC gp, expresses
non-classical HLA-E and HLA-G
● transfer of small doses of fetal antigens in maternal circulation
causes tolerance ... suppressin of TH1 and preference of TH2
immune mechanisms in pregnancy
Rh incompatibility
• Complications in pregnancy: production of anti-RhD
antibodies by RhD- mother carrying an RhD+ fetus
(hemolytic disease of newborns)
• Fetal erythrocytes penetrate into the maternal
bloodstream during pregnancy - a small amount, don´t
immunize
• During childbirth or abortion (after 8 weeks of gestation)
fetal erythrocytes can penetrate into the bloodstream of
mother → immunization, formation of anti-RhD
antibodies
• After childbirth, investigate Rh factor of born child, if is
child Rh+, mother gets up to 72 hours after birth
injection of anti-Rh antibodies (administered after
abortion too)
Rh incompatibility
• Anti-Rh(D) injection, this antibodies bind to RhD Ag on
baby´s red blood cells, this Ag than can´t bind to BCR
and can´t activate B lymphocytes, this immune comlexes
also actively inhibit B lymphocytes
• During next childbirths, if fetus is Rh+ and mother
produce anti-Rh antibodies, this Abb destroy red blood
cells of fetus, which can lead to fetal death, or in severe
postpartum anemia (anemia neonatorum) and neonatal
jaundice (icterus gravis neonatorum)
• For each pregnant woman during the first trimester
investigate blod Rh factor and the presence of
antibodies, in Rh- women performed a test for antibodies
also in II. and III. trimester
Immunopathological
reactions
Classification by Coombs and Gell
Immunopathological reactions: immune response, which
caused damage to the body (secondary consequence of defense
responses against pathogens, inappropriate responses to
harmless antigens, autoimmunity)
IV types of immunopathological reactions:
Type I reaction - a response based on IgE antibodies
Type II reaction - a response based on antibodies, IgG and IgM
Type III reaction - a response based on the formation
of immune complexes
Type IV reaction - cell-mediated response
Immunopathological reactions based on
antibodies IgG and IgM (reaction type II)
Cytotoxic antibodies IgG and IgM:
● complement activation
● ADCC
● binding to Fc receptors on phagocytes and NK cells
Examples of immunopathological reaction
Type II
• Transfusion reactions in administration of
incompatibile blood:
binding of antibodies to antigens on erythrocytes →
activation of the classical way of complement → cell
lysis
• Hemolytic disease of newborns:
caused by antibodies against RhD antigen
Autoimmune diseases:
● organ-specific cytotoxic antibodies (antibodies against
erythrocytes, neutrophils, thrombocytes, glomerular basement
membrane ...)
● blocking or stimulating antibodies
Graves - Basedow's disease - stimulating antibodies against the
receptor for TSH
Myasthenia gravis - blocking of acetylcholin receptor→ blocking
of neuromuscular transmission
Pernicious anemia - blocking the absorption of vitamin B12
Antiphospholipid syndrome - antibodies against fosfolipids
Fertility disorder - antibodies against sperms or oocytes
Immunopathological reactions based on immune
complexes formation (reaction type III)
● caused by IgG antibodies → bind to antigen → creation
of immune complexes
● immunocomplexes - bind to Fc receptors on phagocytes
- activate complement
● immune complexes, depending on the quantity and structure,
are eliminated by phagocytes or stored in tissues
● pathological immunocomplexes response arises when is a large dose
of antigen, or antigen in the body remains; arise 10-14 days after
aplication of Ag and induced inflamation can get to chronic state
● immune complexes are deposited in the kidneys (glomerulonephritis),
on the surface of endothelial cells (vasculitis) and in synovie joint
(arthritis)
Serum sickness
● the therapeutic application of xenogeneic
serum (antiserum to snake venom)
● creation of immune complexes and their
storage in the vessel walls of different organs
● clinical manifestations: urticaria, arthralgia, myalgia
Systemic lupus erythematosus
● antibodies against nuclear antigens, ANA, anti-dsDNA
Farmer's lung
● IgG antibody against inhaled antigens (molds, hay)
Post-streptococcal glomerulonephritis, cryoglobulinemia,
revmatoid arthritis, post-infectious arthritis
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