Transplant Rejection: Causes, Types and Prevention

Through this project I have researched transplants of organs, cells and tissues, Transplant rejection, the Human Immune System and the role of antibodies. Transplatation is the process where healthy cells, tissue or organs are moved from one site to another. There are different types of transplants and many problems that can occur with transplantation. The largest threat to a successful organ transplant is the Human Immune System, because it rejects the transplant.

The role of the human immunity system is to protect the body from harmful, infecting agents. It destroys the transplant recognizing it as foreign and a potential treat to the body. This is known as Transplant Rejection.

There are many different types of Transplant Rejection, each with there own diagnosis methods and symptoms. There are different ways of prevention and treatment, including tissue typing to determine the most appropriate donor-recipient match and using Immunosuppressant drugs that suppress the immune system of the recipient.

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There are two kinds of immunity in a human. The body’s first line of defence is the Innate Immunity and the specific response to the invaders is the Adaptive Immunity. Many white blood cells form the main components of the immune system and they identify and destroy invading agents.

There are also different types of immune responses including the Humoral immune response. Antibodies, Y-shaped proteins, form part of the Humoral response. The structure of all antibodies are very similar, except for a small unique region at the ends of the two arms of the Y used for recognising agents. Antibodies can destroy the foreign material or help destroy them by tagging it for attack by other parts of the immune system.

Antibodies are very important in transplant rejection, because they form part of the mechanism that rejects the organ or tissue and are one of the most important cells of the Human Immunity System. They help lead to Transplant Rejection and the destruction of the transplanted organ or tissue.

INDEX (Jump to):

Introduction

Hypothesis

Transplants

Types of Transplants

Problems With Transplantation

Transplant Rejection

Types of Transplant Rejection

Diagnosis and Symptoms

Prevention and Treatment

Potential Further Studies

The Human Immune System and Antibodies

Types of Immune Responses

Conclusion

Bibliography & Referencing

INTRODUCTION:

The role of the Human Immunity System is to protect the body from harmful, infecting agents. This protection is very important to keep our bodies healthy and functioning at the best it can, but this protection is also the largest problem in organ and tissue transplants.

Transplantation has replaced many people damaged organs with healthy organs and is used to cure many tissue and cell diseases. The Human Immunity System is the largest threat to successful organ and tissue transplants, but why does the Human Immunity reject the transplanted organ or tissue? And is it possible that transplant rejection can be prevented?

The body is constantly under attack from harmful substances that can cause damage and destruction to the human body, but we are protected. The human immunity system is body’s natural defence mechanism. What causes an immune response? And how does the immune system respond to foreign materials?

Antibodies are an important part in the human immunity system. They can recognize, neutralize and destroy harmful materials, but what exact role does an antibody play in human immunity? Where and why are antibodies produced?

Through this project I will explore transplants, transplant rejection, human immunity and the role of antibodies and finally prove or contradict my hypothesis.

HYPOTHESIS:

Antibodies do not play a role in the rejection of a transplanted organ or tissue.

Transplants

Transplatation is the action of healthy cells, tissue or organs that are transplanted (grafted) from one site to another. A transplanted organ can replace a recipient’s damaged, malfunctioning or absent organ and grafting of cells and tissue can also cure many diseases.

A kidney (most common), heart, lungs, pancreas, liver, skin, cornea, blood, blood vessels, bone marrow, stem cells, cord blood, intestine, stomach, testis, thymus, bones, tendons, heart valves and veins, hand, Islets of Langerhans and ovaries can now be transplanted. The transplanted organ or tissue is commonly known as a graft.

While the lack of organs for transplantation remains an obstacle, the biggest challenge for transplantation is the immune system. It destroys a transplanted graft recognizing it as foreign and a potential treat to the body. [2][7][9][11][12][13][14][15][16][17][18][19][20][21][22]

Types of Transplants

Autografts: Grafts of tissue from one area of the body to another part e.g. Skin transplants, vein extractions, etc. Autografts are not foreign tissue and therefore there is no immune reaction.

Allografts: Grafts between members of the same species. Most organ transplants are allografts. Because of genetic differences between the organ and the recipient, the recipient’s immune system will identify the organ as foreign and attempts to destroy it, causing transplant rejection.

Isografts: Forms part of allografts and are grafts between genetically identical individuals. Isografts do not trigger an immune response.

Xenografts/ Xenotransplantation: Grafts between members of different species. E.g. the use of organs from other animals, like chimpanzees, baboon and pigs. In Xenografts there is a large risk of rejection and diseases carried in the tissue. [2][7][9][19][20][22]

Problems with Transplantation

Graft/transplant rejection: The immune system, recognizing the transplanted graft as foreign, will cause a rejection of the graft.

Graft-versus-host disease (GVHD): T-cells, in the graft from the donor, identify the tissues of the recipient as a foreign antigen and mounts an immune attack against them. This is prevented by removing all T-cells in the graft before transplantation.

In rare cases the donated organ may be infected and transmit an agent to the recipient. E.g. TB, rabies, syphilis, hepatitis B, HIV and many other diseases. To prevent this, potential donors are tested for these infections before the transplantation. [2][12][19]

Transplant Rejection

Transplant rejection is also know as Graft Rejection and organ or tissue rejection.

Transplant Rejection occurs when a transplanted organ or tissue is not accepted by the body of the recipient, because the immune system of the recipient attacks and tries to destroy the transplanted organ or tissue. The body identifies the graft as foreign material and therefore triggers a rejection.

This is expected because the Human Immunity System’s purpose is to protect the body by identifying and destroying foreign material that are potentially harmful. These harmful substances have proteins called antigens on their surfaces, when the immune system identifies these antigens as foreign, it will start to attack them.

The degree and type of response varies according to the type of transplant and the organ or tissue being transplanted. Certain sites in the body are immune privileged, which means they are protected from attack, because immune cells and antibodies do not reach them. The anterior chamber of the eye, the testes and the brain are all immune privileged.

Using the patient’s own tissue for autografts or tissue from an identical twin, isografts, when available prevents transplant rejection as the recipient sees the transplant as “self”, not as foreign and therefore does not mount an attack. Using a relative (sibling) as a donor is also recommended, because they may have inherited some of the same histocompatibility antigens and therefore the immune response may not be as strong. [2][3][4][7][8][11][12][23]

Types of Transplant Rejection:

Hyperacute Rejection

Hyperacute Rejection is a rare humoral & complement-mediated response in recipients with pre-existing antibodies to the donor. This reaction occurs immediately after the transplantation. No treatment is available for it and the graft must be removed quickly to prevent a severe systemic inflammatory response or death.

Acute Rejection

Acute rejection usually begins one week after the transplant, but it can occur months to years after transplantation. The new organ will be incapable of working at full efficiency. A single episode of acute rejection is not dangerous, if it recognized and treated it rarely leads to organ failure.

Acute rejection occurs to some degree in all transplants and is caused by mismatched HLA. The Immune system will recognize the graft as foreign and will mount an attack against it. Acute rejection is a form of Cell-mediated response.

Humeroral Rejection

Humeroral Rejection is mediated by antibody and complement Immunity. It can occur immediately or during the first week after the transplantation. The antibodies are preformed antibodies or anti-donor antibodies that have developed after transplant.

Chronic Rejection

Chronic Rejection is the rejection against a graft due to chronic inflammatory and immune response. This rejection occurs over time (sometimes years after the transplant) and may occur from repeated episodes of acute rejection or for other causes not understood.

Chronic Rejection is rare and is both antibody & cell-mediated immune responses. Chronic rejection is irreversible and there is no successful treatment. Eventually the donor organ is lost, leading to re-transplant or death. [3][7][8][23]

Diagnosis and Symptoms

Diagnosis of transplant rejection relies on clinical data, including signs and symptoms, lab testing and a tissue biopsy to confirm that the graft has been rejected. The biopsy is interpreted by a pathologist who notes changes in the tissue that suggest rejection. E.g. presence of T-cells and other cell types that may be helpful in diagnosing the type of rejection and any evidence of structural injury or injury to blood vessels in the transplanted tissue.

The symptoms of transplant rejection vary depending on the organ or tissue transplanted, but general symptoms include the organ not functioning properly, general discomfort, uneasiness or ill feeling, pain or swelling in the location of organ (rare) and fever (rare). [1][23]

Prevention & Treatment

Tissue Typing

Transplant rejection can be reduced through serotyping (tissue typing or crossmatching) before the transplantation to identify the antigens it contains and to determine the most appropriate donor-recipient match. ABO blood typing or HLA (Tissue antigen) typing is performed to ensure that the organ or tissue is as similar as possible to the tissues of the recipient.

The antigens responsible for rejection of tissues are called histocompatibility antigens. These antigens are encoded by genes on chromosome 6, called the Major Histocompatibility Complex (MHC). The MHC is called the Human Leukocyte Antigen (HLA) system in humans. HLA are present on all cells of the body. Each individual has a unique combination of HLA and matching as many histocompatibility antigens will minimize the size and speed of rejection.

MHC molecules present antigens to the T-cells of the immune system. When a foreign material enters a body cell, the MHC molecules inside the body cell bind to the antigen and transport it to the body cell’s surface. The antigen can now be recognized by a T-cell.

Immunosuppressant Drugs

Immunosuppressant drugs can treat and prevent transplant rejection. The drugs suppress the immune system of the recipient and are usually necessary for all transplants to prevent the graft from being rejected. The drugs should be used for the rest of the transplant recipient’s life.

Most immunosuppressive drugs have the disadvantage of being non-specific and they result in suppression of the entire immune responses and therefore placing the recipient at a higher risk of infections. It is needed to develop more specific immunosuppressive drugs that will suppress only the responses that attack the graft, without dangerous side effects.

Drugs like azathioprine (Imuran), methotrexate, cyclophosphamide, prednisone, belatacept, corticosteroids, cyclosporine A, tacrolimus, prednisolone, mycophennolate mofetil, antithymocyte globulin (ATG) and rapamycin are routinely used in different combinations for a safe level of immunosuppression.

Side effects of immunosuppression drugs include infections, as the immune system is vital to protect us from infectious agents (bacteria, viruses, fungi, etc). Usually the infections can be controlled by the appropriate antibiotic, antiviral drug, etc. The chance of Cancer is also increased with the use of immunosuppression drugs. [1][2][5][6][7][8][12][16][19][23]

Potential Further Studies

Demi-Lee Brennan, an Australian whose body changed blood type and adopted the immune system of her donor after a liver transplant. Her body no longer rejects the transplanted liver. Her case is unique and scientists are interested in finding out how this occurred. Duplication of this would be a potential solution to transplant rejection.

Some grafts survive despite the presence of anti-donor antibodies. This acquired resistance to antibody-mediated damage is known as Accommodation and is poorly understood. [6][8]

The Human Immune System and Antibodies

The immune system recognizes as foreign and attacks anything different from your normal body tissues. Even substances that are only slightly different, for example a transplanted organ or tissue, are considered foreign invaders.

The immune system uses histocompatibility antigens to recognize material as self or foreign. Antigens occur on the surface of every cell and the immune system will attack anything that does not display the antigen of that individual. The immune system cannot tell if the foreign material is harmful or not, just that it is different. The transplanted organ or tissue is different and therefore the immune system will try to destroy it.

There are two kinds of immunity in a human, Innate Immunity and Adaptive Immunity. The body’s first line of defence against invaders is the Innate Immunity. It is provided by barriers like tears, mucus, skin, saliva and the rapid inflammation of tissue. If an invader gets past the Innate Immunity, the immune system will make a customized defence, the Adaptive Immunity. It is a specific response depending on the specific invader and it has a memory, which allows it to respond better to the specific invader if it attacks again. The Adaptive Immunity does not attack normal body components, only substances it recognizes as non-self.

White blood cells (leukocytes) are the main component of the immune system. Macrophages, a type of white blood cells, surround and eat invading materials. Macrophages can also attach to themselves to invading agents and transport them to another part of the immune system to be destroyed. Lymphocytes are specialized white blood cells that identify and destroy invading antigens. Each lymphocyte has a unique antigen receptor on its surface that can bind to a matching antigen on the surface of the foreign invader. They constantly travel throughout the body looking for invaders. All lymphocytes begin as stem cells in bone marrow, but they mature in two different places.

Several lymphocytes mature in the bone marrow and they are called B-lymphocytes (B-cells). B-cells form Plasma cells that make antibodies. Each B-cell has a unique receptor on its membrane, called B-cell receptor (BCR) that is designed to fit a specific antigen. When the BCR binds to an antigen molecule, the B-cell surrounds it and breaks it up. The result is the histcompatibilty molecules and then the body B-cell can identify the antigen.

Other lymphocytes called T-lymphocytes (T-cells) mature in the thymus. Some T-cells called cytotoic or Killer T-cells directly destroy cells that are displaying a certain antigen on their surface. Other T-cells, Helper T-cells, regulate the immune system by controlling the strength of immune responses. [1][3][5][6][7][8][10][11][23]

Types of Immune Responses

Humoral Immune Response

The Humoral response attack invaders that act outside of cells, like bacteria and poisons.

When an invader antigen enters the body, Macrophages take the antigen and attach it to MHC molecules. The MHC molecules display the antigen to the T-helper cells and they attach to the presented antigen. This stimulates the T-helper cells to divide and produce interleukins. The Interleukins activate a B-cell that has bound the antigen. The activated B-cells then divide and secrete antibodies.

Antibodies, also called immunoglobulins (lg), are Y-shaped proteins and they are found in blood and other bodily fluids of vertebrates. Antibodies are produced by a kind of white blood cell, called a plasma cell.

Surface immunoglobulin are attached to the membrane of the effector B-cells, while antibodies are the secreted into the bloodstream and body cavities. The membrane-bound form of an antibodies is forms part of the BCR on B-cells.

The general structure of all antibodies are very similar, except for a small region at the ends of the two arms of the Y used for binding antigens. This allows many different antigen binding sites to exist between the antibodies, allowing the immune system to recognize a wide diversity of antigens.

The base of the Y determines how the antibody will destroy an antigen or foreign material. Antibodies into are classified into 5 classes/isotypes: lgM, lgG, lgA, lgD and lgE. They perform different roles and form part of the immune response against foreign objects.

The secreted antibodies bind can the antigen and destroy it. Antibodies may also stop the harmful effects of an antigen by attaching to it and neutralizing it. Antibodies also help destroy antigens by tagging it for attack by other parts of the immune system.

Cell-mediated Immune Response

The Cell-mediated Response attacks invaders, like viruses, that reproduce inside cells. It also destroys cells that cause the growth of improper structures, like cancers.

After an invader antigen enters the human body, Macrophages attach the antigen to MHC molecules. The MHC molecules present the antigen to the T-helper cells and they bind the antigen, which motivates the T-helper cells to divide and secrete interleukins. The Interleukins activate killer T-cells. Killer T-cells directly destroy the cell/s that are infected with or that are producing a certain antigen. [3][7][8][10][11]

CONCLUSION:

My Hypothesis that antibodies do not play a role in the rejection of a transplanted organ or tissue is incorrect. Antibodies are very important in transplant rejection, because they form part of the mechanism that rejects the organ or tissue and they are one of the main components of the Human Immunity System.

When the healthy organ or tissue is transplanted into the body of the recipient, it does not have the same tissue antigens of the recipient’s body. Each human has unique tissue antigens, therefore a perfect match is seldom found.

Antibodies form part of humoral rejection response to the transplanted organ or tissue. They are the main element in recognizing a foreign agent, because they have unique antigen binding sites. Antibodies especially play a role in Hyperacute, Humeroral and Chronic Transplant Rejection, as they are all humoral-mediated rejections.

Anti-Donor antibodies are secreted by plasma cells after the T-helper cells have collected the transplant’s antigen and identified it as foreign and non-self. Pre-existing antibodies circulate through the bodily fluids of the human body looking for foreign material to recognize. Some antibodies also form part of the membrane receptor of the B-cells used to identify and recognize antigens of the transplanted organ or tissue.

After the antibodies have bond to the foreign antigen of the transplanted organ or tissue, therefore recognizing it, it will decide how to destroy the organ or tissue or if it will tag it for attack from other parts of the immune system. Leading to Transplant Rejection and the destruction of the transplanted organ or tissue.

BIBLIOGRAPHY & REFERENCING:

Websites:

http://www.nlm.nih.gov/medlineplus/ency/article/000815.htm, “Transplant Rejection”, Medline Plus, 23 February 2010, David A. Kaufman, MD, Section Chief, Pulmonary, Critical Care & Sleep Medicine, Bridgeport Hospital-Yale New Haven Health System, and Assistant Clinical Professor, Yale University School of Medicine, New Haven, CT.

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/T/Transplants.html, “Organ Transplants”, 1 November 2009

http://www.chfpatients.com/tx/txrejection.htm, “Transplant Rejection”, CHF Patients, 3 June 2002

http://www.uihealthcare.com/topics/medicaldepartments/surgery/rejection/index.html, “Rejection: Organ Transplantation”, UI Healthcare, 7 August 2006, University of Iowa Hospitals and Clinics

http://immunology.suite101.com/article.cfm/why_organ_transplants_fail, “Why Organ Transplants Fail”, Immunology, 5 June 2009, Jitendra Rathod

http://discoverysedge.mayo.edu/abo_posxmatch/index.cfm, “Overcoming Antibody Barriers to Kidney Transplant”, Discovery’s Edge, 2010, Mayo Foundation for Medical Education and Research

http://emedicine.medscape.com/article/432209-overview, “Immunology of Transplant Rejection”, eMedicine, 28 July 2009, Prashant Malhotra, MBBS, Fellow, Division of Infectious Diseases, North Shore University Hospital

http://en.wikipedia.org/wiki/Transplant_rejection, “Transplant Rejection”, Wikipedia, 27 March 2010

http://en.wikipedia.org/wiki/Organ_transplant, “Organ Transplant”, Wikipedia, 21 March 2010

http://en.wikipedia.org/wiki/Antibody, “Antibody”, Wikipedia, 23 March 2010

Books:

Westen, Trevor. 1976. The Hamlyn Family Medical Dictionary. Hong Kong: Toppan Printing Co. p16,187-188,367-368.

Danovith, Gabriel. 2001. Handbook of Kidney Transplantation Third Edition. Philadelphia: Lippincott Williams & Wilkins. p17-61,146-162.

Malan, Marais.1968. Heart Transplant. Johannesburg: Voortrekkerpers. p21-36.

Magazines:

Meyer, Rilette. “Die grootste geskenk”. Vroukeur. August 2009, p22

Unknown. “‘n Geskenk van lewe”. Vroukeur. August 2009, p31

Salzwedel, Ilse. “Bloed Bande”. Huisgenoot. Winter 2008, p22-28

Ramsamy, Prevashni. “The Ultimate Donation”. February 2006, p30-32

Newspapers:

Unknown. “Orgaanskenkings – gee die geskenk van lewe”. Die Burger. 29 September 1998

Hudsen, Mari. “So verloop die proses van orgaanskenking”. Die Burger. 14 August 2000, p5

Gerber, Jan. “Tekort aan skenkers van organe”. Die Burger. 14 April 2007

Wessels, Elsa. “Nalaat van organe vir oorplanting is grootste geskenk denkbaar”. Die Burger. 5 August 1998, p13

Kees, Revona. “Orgaanskenkers kan talle lewens red”. Die Burger. 31 August 2005, p10

Medical Journals:

Chan, Laurence. 2000. “Transplant Rejection and it’s Treatment”. Chapter 9 (pg. 9.1 – 9.13).

Cover Picture and Background: Source: http://upload.wikimedia.org/wikipedia/en/a/ab/Outline-body-aura.png