Transplantation Immunology

non-self, largely through MHC (HLA) molecules

what does the immune system recognize transplanted tissues as?

compatibility between donor and recipient MHC, ABO, and minor histocompatibility antigens

what does a successful transplantation depend on?

advances in immunogenetics and immunosuppression

what has significantly improved graft survival?

MHC molecules

what are the major determinants of transplantation rejection?

chromosome 6

where is the MHC/HLA system located?

as haplotypes

how are MHC/HLA molecules inherited?

• HLA-A

• HLA-B

• HLA-C

which HLA molecules are class 1?

on all nucleated cells; present peptides to CD8 cytotoxic T cells

what characterizes Class 1 MHC?

• HLA-DR

• HLA-DQ

• HLA-DP

which HLA molecules are Class 2?

on antigen-presenting cells (B cells, macrophages, dendritic cells, endothelial cells); interact with CD4 helper T cells

what characterizes Class 2 MHC?

ABO is the most important

what is an exception to matching class 1 and 2 antigens for transplantations, in the case to kidney transplants?

all HLA matches

what is needed for bone marrow transplant?

needed for cytotoxic T lymphocytes to interact with target cell

what is the purpose of Class 1 gene products?

needed for T helper cells to interact with antigen-presenting cells and B cells

what is the purpose of Class 2 gene products?

substitute or replace a diseased organ or tissue with a functional one

what is transplantation?

transplant tissues or organs

what is a graft?

donor and host are the same person

what is an autograft?

skin grafts

what is an example of an autograft?

transplant between identical twins

what is syngraft (isograft)?

no rejection

what is the risk of rejection of autografts and syngrafts?

an allogenic donor—between individuals of the same species, genetically different

what is allograft?

rejection if not well matched—immunosuppressive therapy used to keep body from rejecting graft

what is the risk of rejection with allografts?

allograft (homograft)

what is the most common type of transplant?

transfer of tissue from one species to another—baboon heart→ human

• some cow or pig valves are used to treat aortic and mitral valve defects

what is a xenograft (heterograft)?

very high; experimental

what is the rejection risk of xenografts?

• hyperacute

• acute

• chronic

what are the types of graft rejection?

within minutes to hours

when does a hyperacute graft rejection occur?

with xenografts or with ABO incompatibility

when is a hyperacute graft rejection observed typically?

preexisting antibodies

what causes a hyperacute graft rejection?

recipients are tested for antibodies

how can hyperacute graft rejection be prevented?

acute graft rejection

what is the most common reaction during the first year post-transplant?

over days to weeks—may last life of graft

when does an acute graft rejection occur?

graft tenderness and fever

what are symptoms of acute graft rejection?

both cell mediated and antibody mediated immunity

what does acute graft rejection involve?

CD4 and CD8 are activated→CD4 produces cytokines and induces delayed type hypersensitivity reactions; CD8 destroys grafted tissue

what is the mechanism of acute graft rejection?

induces B cell to make antibody to HLA-DR

• damage due to complement activation or Antibody Dependent Cellular Cytotoxicity (ADCC)

what is the function of CD4 during an acute graft rejection?

immunosuppressive therapy

what can usually reverse acute graft rejections?

months to years following transplant

when do chronic graft rejections occur?

cell mediated and antibody mediated immunity

what does chronic graft rejection involve?

fibrosis and ateriosclerosis (loss of elasticity, impaired circulation)

what characterizes a chronic graft rejection?

no

is chronic graft rejection reversible?

ABO typing

what does the first stage of tissue typing involve?

HLA typing

what does the second stage of tissue typing involve?

RBC and graft blood vessels

where are ABO AGNs located?

serological detection of class I and II molecules—known antibodies (from multiparous women; or monoclonal), patient cells, complement

what is the lymphocytotoxicity test?

• use microtiter plate

• antibody placed in individual well

• mix patient cells

• cells are separated by gradient centrifugation

• lymphocytes for class I detection

what is the lymphocytotoxicity test procedure?

no, because it uses an antisera of poor quality (multiparous women)

is lymphocytotoxicity the best method of determining class II antigens?

PCR

what have most labs switched to instead of lymphocytotoxicity serology?

B cells

what cells are used for Class II detection?

determines DNA sequence coding for HLA DR, DQ, & DP

what is the function of PCR?

compatibility

what tests are not needed for corneal transplants?

damaged cornea is replaced by a cornea from eye of a human cadaver

what is a corneal transplant?

corneal transplant

what is the most common type of human transplant surgery that also has the highest success rate?

autografts and allografts

what do bone grafts use a combination of?

it is degraded and eliminated when healing is complete

what happens to the allograft material used in bone grafts?

permanent

how long does an autograft skin graft last?

new epidermis is “grown to order” in laboratory—cultured epithelial autograft

what is an epicel?

temporary; quickly rejected by patient’s immune system

how long do allograft skin grafts last?

nonimmunogenic skin replacements

why is there a decreased demand for allograft skin grafts?

• temporary wound covering to decrease pain and augment healing

• permanent skin substitute to add or replace the remaining skin components

what are the nonimmunogenic skin replacements?

kidney

what is the most often transplanted solid organ in the United States?

90% after one year with proper matching and immunosuppression

what is the success rate of kidney transplants?

ABO—-more important than HLA matching

what is more important in matching with kidney transplants?

multiple blood transfusions to increase tolerance

what can be done prior to kidney transplantations to increase survival afterwards?

• Johns Hopkins Transplant Center has pioneered a method of ABO-incompatible renal transplantation using plasmapheresis/Rituximab

• accommodation—anti-A/B antibody levels may return to normal levels without graft rejection

what is the exception of ABO matching of kidney transplantations?

• A, B, C, DR, & DQ testing for living donors

• ABO and HLA testing for cadaver donor

what is the HLA typing with kidney transplants?

2 days

how long can kidneys tolerate being outside the body?

if the number of HLA mismatch is less than 1

what can improve survival of kidney transplants?

• ABO blood group

• physical size of the donor and recipient

• seriousness of the recipient’s illness

what is more important than HLA typing with liver, heart, and lung grafts?

within 4 hours

when does a heart have to be transplanted?

ABO and HLA-DR match

what does a pancreas graft need?

full pancreatic or isolated islet cell transplantation

what does a pancreas graft include?

simultaneous kidney/pancreas transplants

what might patients with diabetes mellitus have?

Isabelle Dinoire in 2005

who had the world’s first partial face transplant?

Karl Merk in 2008

who was the first successful arm transplant?

therapy for a number of malignant and nonmalignant hematologic disease

what are bone marrow transplants used as?

hematopoietic progenitor cells are given intravenously—cells may be collected directly from bone marrow, from umbilical cord blood, or from peripheral blood

how is bone marrow transplanted?

HLA matching essential for survival; ABO typing not as significant

what is essential for a successful bone marrow transplant?

they are treated with high doses of chemotherapy and sometimes radiation to destroy their own bone marrow

what is done before the recipient can receive a bone marrow transplant?

autologous and allogenic

what are the types of bone marrow transplants?

• remove patient’s bone marrow, freeze and return to patient after patient is treated

• rejection is not a problem

what characterizes autologous bone marrow transplants?

• HLA typing: need A, B, & C to match

• graft v host disease

what characterizes allogenic bone marrow transplants?

recipient hematopoietic and immune cells are replaced by donor cells

what happens if the bone marrow transplant is successful?

peripheral blood progenitor cells

what is increasingly being used in place of bone marrow?

• collect larger amounts

• more rapid hematologic recovery

• eliminate surgical procedure/anesthesia risk

• reduced transplant cost

what are advantages to peripheral blood progenitor cell transplants?

• donors given growth factors to increase the amount of stem cells released into blood stream

• stem cells removed by apheresis and given intravenously

what is the procedure of peripheral blood progenitor cell transplants?

suppress T cell responses and inflammation

what is the treatment of rejection of peripheral blood stem cell transplants?

• cyclosporine

• azathioprine

• steroids

what are the nonspecific immunosuppressive agents used to treat/prevent rejection of peripheral blood stem cell transplants?

decreases expression of IL-2 receptors and decreases cytokine production by T helper cells

what is the function of cyclosporine?

prevents cell proliferation

what is the function of azathioprine?

anti-inflammatory—affects activated macrophages and decreases expression of HLA antigens

what is the function of steroids?

decreases lymphocytes

what is the function of specific therapy in preventing/treating peripheral blood stem cell transplant rejection?

• anti-lymphocyte globuliln

• monoclonal anti-CD3, anti-CD4, anti-IL-2, etc

what are some specific therapies with prevention/treatment of rejection?

A, B, C, DR match

what is looked for if donor/recipient are related?

A, B, C, DR, DQ, DP

what is looked for if donor/recipient are unrelated?