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Transplantation Immunology
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Transplantation Immunology Lecture objectives Students are ...

May 24, 2015

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Page 1: Transplantation Immunology Lecture objectives Students are ...

Transplantation Immunology

Page 2: Transplantation Immunology Lecture objectives Students are ...

Lecture objectives

Students are expected to understand:

•Types of rejection (hyperacute, accelerated acute, acute and chronic)

•Immunological mechanisms of transplantation rejection

•ABO and other Blood types

•GVHD

•Immunosuppressive drugs

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22. Transplantation immunology

a. Definitions of autografts, syngrafts, allografts, and xenografts

b. The role of MHC antigens (alloantigens), minor histocompatibility antigens and

ABO blood type in graft acceptance and rejection

c. Mechanisms of graft rejection

(1) Hyperacute rejection: recipient has pre-existing antibodies to ABO

antigens or HLA antigens; occurs within minutes to hours; mechanism by Types II and III

reactions.

(2) Accelerated Acute: occurs within a few days; mediated by sensitized T

cells (CMI)

(3) Acute: occurs within the second week; T cells (CMI) become

sensitized to alloantigens (HLA antigens)

(4) Chronic: occurs months to years after the transplant; multiple

immunologic mechanisms; chronic inflammation, pro-inflammatory cytokines, and

increased adhesion molecules on endothelium important

CORE

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Transplantation immunologyd. Graft-versus-host reaction (acute and chronic)

(1) Immunologic mechanisms and types of transplants involved

e. Tissue typing, preventing rejection, and inducing recipient unresponsiveness

(1) ABO compatibility(2) Crossmatching(3) HLA typing(4) Immunosuppressive drugs

(a) Azathioprine(b) Cyclosporin(c) Corticosteroids(d) Anti-lymphocyte antibodies (polyclonal anti-T,

monoclonal anti-CD3, 4, 8)

CORE

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f. Clinical transplantation

(1) Kidney

(2) Liver

(3) Pancreas

(4) Heart

(5) Lung

(6) Bone marrow

CORE

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Tests for pathogensHuman Immunodeficiency Virus (HIV-1/2), Hepatitis B (HbsAg)Hepatitis C (HCV). Also CMV, HTLV-1, syphilis, Epstein-Barr virus, and HTLV-2

Tests for compatibility:HLA (HLA-A, HLA-B and HLA-DR )and ABO

Tests before transplantation

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Terminologies

•Autograft: transplantation of self tissues to a different site of the body(e.g. skin graft in burn patients)

•Syngeneic transplant: between genetically identical individuals(Between identical twins)

•Allogeneic transplant : between genetically different individuals(This is most common)

•Xenograft: transplantation between different species (e.g. Pig to Human)

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Transplantation Immunology

Allogenic immune responses after transplantation are caused by genetic differences (e.g. MHC and ABO) between donors and recipients.

Immune system A Immune system B

Organ

Recipient (B type blood)

TT APC APC

MHC-a MHC-bTCR-a TCR-b

Ab to A-RBCA-RBC

Donor (A type blood)

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Hyperacute (immediate) reaction

Response to ABO antigens (and/or MHC class I/II molecules) expressed by Endothelial cells

1. Preexisting antibodies to A/B antigen in recipients bind A/B antigens on endothelial cells of transplanted organs, and induce acute rejection.

2. This can be caused by pre-existing antibodies to MHC I/II molecules too, which can arise from pregnancy, blood transfusion or previous transplantation. In this case, fetal cells induce antibody formation in the mother

Graft failure

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21. Human Blood Group Antigens

a. ABO blood groups (structure, inheritance, and naturally occurring antibodies)

b. Rh blood groups (e.g. erythroblastosis fetalis)

CORE

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In blood transfusion and organ transplantation, donors and recipients should be matched for the A/B/O blood antigens

RBCs don’t express MHC molecules but express different types of carbohydrate antigens (A,B, and O). These antigens are similar to bacterial cell surface antigens. Therefore, most people possess antibodies that react against the antigens except the antigen they express themselves. O persons have antibodies to A and B. Anti-A or B antibodies cause complement fixation and rapid clearance of RBC (hemolytic reaction; renal failure) or hyperacute rejection. Similar to TYPE II hypersensitivity reaction.

There is no antibody to O antigen in A, B or AB person because all express the core O antigen.

Remember that self reactive B cells are deleted in the body.

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ABO Blood Group System

Blood Type GenotypesABO EnzymesPresent

RBC AntigensPresent

Serum Antibodies

A AA, AO "H", "A" A, O anti-B

B BB, BO "H", "B" B, O anti-A

AB AB "H", "A", "B" A, B, O none

O OO "H" O anti-A, anti-B

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How Blood Types Are Inherited

AO AB

AA AB OA OB

X

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ABO match for blood transfusion

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Other blood group antigens(minor antigens)

Rhesus: C, D and E

RhD is most important clinically among minor antigens due to its high immunogenicity

RhD+ : 85%; RhD-:15%

Other minor blood group antigens such as Kell, Duffy, and MN are less immunogenic.

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Coomb’s test for blood typing

Serum from individuals of type

Red blood cells of the potential recipient

O Agglutination

A Agglutination

B No agglutination

AB No agglutination

RhD+ No agglutination

Red blood cells from individuals of type

Serum from the potential recipient

O No agglutination

A Agglutination

B No agglutination

AB Agglutination

RhD+ Agglutination

RhD ?OABAB

For blood typing, serums and red blood cells are mixed and incubated.What is the blood type of the recipient?

-

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Jesica’s story:(http://www.usnews.com/usnews/health/articles/030728/28jesica.timeline.htm) This is the sequence of events, as reconstructed by U.S. News, that led to the death of Jesica Santillán at Duke University Medical Center after she received a transplanted heart and lungs

with the wrong blood type.Feb. 6, 2003, evening

The New England Organ Bank can't find a local candidate for a heart and lungs from a donor at Children's Hospital Boston with type A blood. The "match-run list" of candidates shows two possibilities, a child and an adult, at Duke University Medical Center in Durham, N.C. NEOB notifies Carolina Donor Services, Duke's link with the national transplant system. CDS phones Duke. Pediatric heart transplant surgeon James Jaggers turns the organs down for the child listed, but requests them for 17-year-old Jesica Santillán. He does not recall mentioning or discussing blood type. CDS verifies with NEOB that Jesica is not on the match-run list.

Feb. 7, early morningCDS calls the United Network for Organ Sharing in Richmond, Va., which has data on everyone awaiting an organ, to ask if Jesica is wait-listed for a heart and lungs. The CDS coordinator mentions that she has type A blood. She is type O. The donor is type A. A UNOS specialist says she is listed. He does not address the misstated blood type. CDS notifies NEOB that Jesica is listed, and NEOB releases the organs to Jaggers. CDS reports this back to Jaggers.

About 9 a.m.Duke surgeon Shu Lin and a CDS representative fly to Boston. Lin calls Jaggers with a thumbs-up on the condition and size of the donor heart and lungs. Blood type is not mentioned.

11 a.m. The organs are removed and packed in ice. A tag identifies the blood as type A. The organs are flown to Durham.

4:50 p.m.The heart and lungs are transplanted into Jesica.

10 p.m.As Jesica is being closed, Duke's transplant lab reports the mismatch. Antirejection drugs are administered, but the heart and lungs begin to fail. Jesica is put on a heart-lung machine.

Feb. 19, 11:30 p.m.CDS tells Jaggers a type O heart and lungs are available.

Feb. 20, 12:30 a.m.The Santilláns are told that replacement organs are on the way.

5:15 a.m.Jaggers begins the second transplant at 6 a.m.

Feb. 21, 2 a.m.Jesica's brain function rapidly declines.

3 a.m.A CT scan indicates significant brain swelling and bleeding.

9 a.m.Neurological tests show no brain activity.

Feb. 22, 1:25 p.m.Jesica is pronounced brain dead.

5:07 p.m.Jesica's heart stops.

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Acute rejection (within weeks) is caused by effector CD4+ Th1 cells or CD8 T cells responding to HLA differences between donors and recipients (similar to TYPE IV hypersensitivity reaction);

Can be prevented by immunosuppressive drugs or anti-T cell antibodies

Accelerated Acute rejection (within days) is mediated by sensitized (memory) T cells induced by previous grafts or exposure.

Acute rejection:

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Cross-reactive recognition for alloreactivityDifferences in MHC molecule expression between a donor and a recipient are said to be allogenic, provoking alloreactions that cause graft rejection..

Acute response to the graft expressing allogeneic MHC

Immune response to foreign antigens

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After transplantation, donor-derived dendritic cells migrate to the recipient spleen and activate recipient T cells, which mediate graft rejection

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MLR (mixed lymphocyte reaction test):Co-culture of blood cells from donor and recipient

More proliferation: More mismatch

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Chronic rejection:

Occurs months or years after transplantation.Thickening of blood vessel walls leading to ischemia

The mechanism is not entirely clear but it may be due to chronic DTH response

localized tissue anemia due to obstruction of the inflow of arterial blood

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HLA matching improves the survival of transplanted kidneys

Matching in HLA A, B, and DR is particularly important

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2 types of alloreactions

Also, there is GVL (=Leukemia) effect against recipients’ leukemic or tumor cells

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Diseases for which bone marrow transplantation is a therapy (BMT)

1. The graft must contain immunocompetent cells (T cells)2. MHC mismatch3. The recipient must be incapable of rejecting the graft(=immunodeficient after radiation/chemo therapy)

For GVHD to occur:

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Pros and Cons of bone marrow transplantation (BMT)Pros:Can cure a number of malignant and genetic diseasesLarge numbers of potential donorsSimple procedure: takes 30 min to take out marrow from a donor from iliac crests of the pelvis under local anesthesia

Cons:1. In GVHD, donor-derived lymphocytes attack host tissues2. Non-functional T cells due to MHC mismatch

Alternative sources of stem cells to minimize GVHD1. Autologous BMT: using self marrow obtained before radiation therapy2. Umbilical cord blood cells, which are enriched with hematopoietic stem cells (CD34+ cells). These fetal cells cause less GVHD.3. Isolated stem cells free of T cells

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Stages of GVHD•  Stage 1 (mild) : a skin rash over less than 25% of the body.

• Stage 2 (moderate) : a skin rash over a more than 25% of the body accompanied by mild liver or stomach and intestinal disorders.

• Stage 3 (severe) : redness of the skin, similar to a severe sunburn, and moderate liver, stomach and intestinal problems.

• Stage 4 (life-threatening) : blistering, peeling skin, and severe liver, stomach, and intestinal problems.

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Xenotransplantation

Pigs: donors of choiceOf similar size, farmed and consumed

Problems: Hyperacute rejection1. Humans have antibodies to pig endothelial carbohydrates2. Pig’s cells are attacked by human complements

Potential solutions:Transgenic pigs expressing human DAF, which prevents

complement reactionTransgenic pigs that don’t express the reactive antigens.

Advantage:MHC molecules of different species are so different from those of

humans that human T cells can not recognize them. So T-cell mediated rejection is mild.

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Immunosuppressive drugs made allogeneic transplantation possible.

They also treat autoimmune diseases.

1. Corticosteroids2. Cytotoxic drugs that kill proliferating lymphocytes3. Microbial immunosuppressive products4. Immunosuppressive antibodies

These drugs limit the normal immune response to pathogens. Patients are susceptible to infection.

As the immune system accommodates the graft, the dose of immunosuppressive drugs is gradually reduced so that patients can have certain defense ability against pathogens

These drugs are used in combination to reduce toxic or side-effects.A long-term side effect is a higher incidence of cancer.Suppress acute rejection mediated by T cells.

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1. Corticosteroids: Prednisolone

Induces expression of many genes, one of which is IkB-alpha that inhibits NF-Kb activation.

Side effects: fluid retention, weight gain, diabetes, loss of bone mineral, thinning of the skin.

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Effects of corticosteroids

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Cyclosporine A, FK506 (Tacrolimus) and Rapamycin

Cyclosporine: a cyclic decapeptide from a soil fungus.Targets calcineurin and blocks NFAT activation

FK506:A macrolide isolated from a soil actinomyceteTargets calcineurin and blocks NFAT activation

Rapamycin:A macrolide isolated from a soil bacterium.Blocks signal transduction from IL-2 receptor

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Cyclosporine A and FK506 inactivate calcineurin (a calcium binding protein), which is required for T, B and granulocyte activation

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Cytotoxic drugs: kill dividing cells

Azathioprine: inhibits DNA replication. Kills not only lymphocytes but also all dividing cells in the body: bone marrow cells, intestinal epithelial cells and hair follicle cells

Cyclophosphamide: cross-link DNA. Side effect includes damage to bladder.

Methotrexate: prevents DNA replication by inhibiting thymidine synthesis

Specificity issue?

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Antibodies specific to human T cells (e.g. anti-CD3) are used to deplete T cells or to suppress their functions :

These antibodies can be made in sheep or goats that have been immunized with human lymphocytes or from mouse hybridoma cells.

Limitation: These non-human antibodies can induce formation of antibodies to the anti-T cell antibodies, which reduces the effectiveness of anti-T cell antibodies after the first use.

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Summary:

Transplantation rejections:

•HyperacuteFactors: preexisting antibodies to ABO and other antigens.

•Accelerated Acute: preexisting memory T cells

•Acute:Factors: MHC compatibility, T cellsGVHD vs. graft rejection.

•ChronicBlood vessel wall thickening.

•Immunosuppressive drugs suppress the acute (and also slow down chronic) rejection processes.