Transplantation Immunology

INTRODUCTION

Transplantation: It is an act of transferring cells, tissues or organs from one site to another. Many diseases can be cured by implementation of healthy organ tissue or cells (a graft) from one individual (donor) to another in need of transplant (host). Alux Carrel reported first systemic study of transplantation in 1908, he interchanged both kidneys in series of nine cats. Organs that can be transplanted are the Kidney, heart, liver, pancreas, lungs, thymus and intestine and tissues include heart valves, bones, tendons, cornea, skin, and veins. The kidneys are the most commonly transplanted organs, followed by the liver and then the heart. A variety of immunosuppressive agents can delay or prevent rejection of transplanted organ, e.g. Calcineurin inhibitor, mTOR inhibitor, Anti-proliferative, corticosteroids and antibodies etc. Different types of grafts/transplants.

Autograft or Auto-transplantation

Self tissue transferred from one body site to another in the same individual. In some cases, autograft is done with surplus tissue, or tissue that can regenerate, or tissues more desperately needed elsewhere, E.g. transferring healthy skin to burnt area in burnt patients and use of healthy old vessels to replace blocked coronary arteries.

lsograft

It is a kind of allograft in which organ or the tissue is transferred from a donor to a genetically identical recipient. In humans, isograft can be performed in genetically identical individuals (monozygous two). Isografts are separated from other types of transplants because they are anatomically identical to allografts, but do not trigger an immune response.

Allograft or Allo-transplantation

Allograft is a transplant of an organ or tissue between genetically different markers of same species. Most human tissue and organ transplants are allografts. The recipient’s immune system will identify the organ as foreign due to genetic difference between the organ and the recipient and attempt to destroy it, causing transplant rejection.

Xenograft or Xeno-transplantation (Greatest Rejection)

A transfer of organ or tissue between different species. For example, Graft of Baboon heart into a human. Xenotransplantation is often an extremely dangerous and serious type of transplant due to increased risk of non-compatibility, rejection and disease carried in the tissue.

IMMUNOLOGIC BASIS OF GRAFT REJECTION

Allograft Rejections Display Specificity and Memory

In allograft rejection, T-cells play a major role. Old grafts and MHC antigens are responsible for the most intense graft rejection. Tissues that are antigenetically similar are said to be histocompatible. They do not produce immunological response that leads to tissue rejection. The various antigens that determine histocompatibility are encoded by more than 40 different loci, but loci responsible for the most vigorous rejection reactions are located within MHC. Organisation of MHC is called H-complex in mice and HLA complex in humans. Various tissue typing procedures used to screen potential donor and recipient.

Initially they are screened for ABO blood group compatibility

Blood group antigens are expressed on RBC’s epithelial cells and endothelial cells.

Ab produced in the recipient against any of these Ag’s present on transplant tissues.

Induced Ab mediated complement lysis of the incompetitive donor cells.

 

Microtoxicity Tests

These tests are used for HLA typing of potential donor and recipient. HLA is based on Ab mediated microcytotoxicity used to indicate the presence or absence of various MHC alleles.

Procedure

WBC’s are potential donor and recipient and are distributed into the series of wells on microtitre plate.

Abs specific for class 1 and class11MHC alleles are added to different wells.

Complement is added to wells and cytotoxicity is accessed by the uptake or exclusion of various dyes by the cells.

WBC’s express MHC allele for which a particular monoclonal antibody is specific, then the cells will be lysed on addition of complement and these dead cells will take up a dye such as trypan blue.

Stages of Graft Rejection

Graft rejection is caused principally by cell mediated immune response to alloantigens (MHC molecules).

CLINICAL MANIFESTATION OF GRAFT REJECTION

Graft rejection has various time courses.

  • Depending on type of tissue or organ groups.
  • Immune response involved.

CLINICAL TRANSPLANTATION

For a number of illnesses, transplant is the only means of therapy. For example, transplanted organs are heart, kidney, pancreas, lung, skin, etc. Immunosuppressive drugs greatly increase short-term survival of transplant but medical problems arise from use these drugs and chronic rejection prevail. Factors responsible with which an organ is transplanted depends on:

  1. Clinical situation in which transplantation is indicated
  2. Availability of tissue or organ
  3. Difficulty of performing transplantation and caring for post transplantation patient.

Heart Transplantation

Heart transplantations is used to remove a damaged or diseased heart and replaces it with a healthy one. The healthy heart comes from a donor who has died. Heart transplants are now the third most common organ transplant operation in the U.S. Doctors may recommend a heart transplant for heart failure caused by: Coronary artery disease, Cardiomyopathy (disease of the heart muscle), Heart valve disease and multiple congenital heart defects in babies.

Kidney Transplantation

A kidney transplant is an operation that replaces a diseased or damaged kidney from the body. The transplanted kidney takes over the work of the two kidneys that failed. During a transplant, the surgeon places the new kidney in recipient lower abdomen and connects the artery and vein of the new kidney to recipient’s artery and vein. Often, the transplanted kidney will start making urine as soon as recipient blood starts flowing through it. But sometimes it takes a few weeks to start working. Many transplanted kidneys come from donors who have died. Some come from a living family member. The wait for a new kidney can be long. Immunosuppressant is usually required to prevent transplant rejection.

Liver Transplantation

Liver transplantation removes the diseased liver and replaces it with a healthy one. Most transplant livers come from a donor who has died. Sometimes a healthy person donates part of his or her liver for a specific patient. In this case the donor is called a living donor. The most common reason for transplantation in adults is cirrhosis (healthy liver cells are killed and replaced with scar tissue) and in children is biliary atresia (a disease of the bile ducts).

Lung Transplantation

Lung transplantation is surgery to replace one or both diseased lungs with healthy lungs. During the operation, the surgeon makes a cut in the chest and removes the diseased lung. The surgeon then sews the new lung to the main blood vessels and air passage. Lung transplantation is recommended if the disease cannot be controlled by any other way. These diseases include: COPD (chronic obstructive pulmonary disease), cystic fibrosis, diopathic pulmonary fibrosis interstitial lung disease, Primary pulmonary hypertension. Complications of lung transplantation include rejection of the transplanted lung and infection.

Pancreas Transplantation

A pancreas transplant is surgery to place a healthy pancreas from a donor into a person with a diseased pancreas. A common reason for this type of damage is diabetes. Pancreas transplants can enable people with type I diabetes to give up insulin shots. An experimental procedure called islet cell transplantation transplants only the parts of the pancreas those make insulin. Immuno-suppressant is usually required to prevent transplant rejection.

Skin Transplantation

It is the replacement of damaged or burnt skin in patients with new skin of donor. Skin Transplantation is usually done to treat burn victims. Immunosuppressant is usually required to prevent transplant rejection.

GENERAL IMMUNOSUPPRESSIVE THERAPY

Allogenic transplantation requires some degree of immuno-suppression if the transplant is to survive. The disadvantage of the most of immunosuppressive treatments that they are non specific and result in generalized immunosuppression of response of all allergens. The patient on long term immunosuppressive therapy is at high risk of hypertension, cancer and metabolic bone disease.

  1. Mitotic inhibitors thwart T-cell proliferation
  2. Corticosteroids: e.g., prednisone and dexamethasone are anti-inflammatory agents and are often given to transplant recipient with other immunosuppressents to prevent acute episode of graft rejection.
  3. Fungal metabolites: Many fungal metabolites are immunosuppressant. e.g., Cyclosporin A and FK 506 block the activation of resting T-cells by inhibiting the transcription of genes encoding IL2 and IL-2 receptors. Ripamycin-immunophillin complex block proliferation and differentiation of activate TH cells. Due to profound properties of these agents, they are used in transplantation of heart, liver, kidney and bone marrow.
  4. Total lymphoid irradiation eliminates lymphocytes. X radiation can be used to eliminate lymphocyte in transplant recipient just before grafting because lymphocytes are extremely sensitive to X-rays.

SPECIFIC IMMUNOSUPPRESSIVE THERAPY

Experimental approaches using monoclonal antibodies offer the possibility of specific immunosuppression. These antibodies may act by:

(a) Deleting the population of reactive cells—The use of antibodies directed against various surface molecules on the cells of immune system can successfully suppress T-cell activity. Depletion of T-cells to suppress graft rejection involves the use of monoclonal antibody to CD3 molecule of TCR complex. Injection of these antibodies causes rapid depletion of mature T-cells. The depletion is caused by the binding of AB coating T-cells to Fc receptor on phagocytic cells, which then phagocytose and deplete T-cells. In another example, Graft survival can be increased by using monoclonal antibodies specific for high affinity IL-2 receptor. As IL-2 receptor expressed only on activated T-cells, exposed to Anti-CD 25 after graft specifically block proliferation of T-cells activated in response to alloantigens of graft. Difficulty with the using antibodies to prolong graft survival in human is that they are generally of non human origin.

(b) Inhibiting co-stimulatory signals leading to anergy in specifically reactive cells—T-cells activation requires interaction of TCR with its ligand and reaction of co-stimulatory receptors with their ligands. Contact between one of the co-stimulatory receptors CD28 on the T-cell and its ligand, B7 on APC, is blocked by reaction of B7 with soluble ligand CTLA-4lg. CTLA-4 is coupled to an IgH chain, which slows its clearance from the circulation. This process specifically suppresses graft rejection without inhibiting the immune response to other antigens.


Questions

  1. Define transplantation. When was the first transplantation done, by whom and in which organ?
  2. What are the different types of transplants/grafts?
  3. Discuss the immunologic basis of graft rejection.
  4. What is microtoxicity test?
  5. What are the different stages of graft rejection?
  6. Discuss the clinical manifestations of graft rejection.
  7. Differentiate between hyperacute, acute and chronic rejections.
  8. Discuss in brief the clinical transplantations.
  9. Write short note on general and specific immunosuppressive therapy.