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Transplant Rejection

The first problem all heart transplant recipients face if they survive surgery is donor organ rejection. Your body ejects any foreign substance that penetrates it - to get rid of invaders. This is a good thing. Unfortunately, your body considers your donor heart an invader and is going to try to eject it from your body.

New theories of how to prevent rejection are emerging. Heavily suppressing the immune system like we do now may actually prevent your body from accepting a new organ. It may be possible to persuade your body to accept a donor organ (tolerance) without heavily suppressing your immune system. This would leave your body able to fight infection normally and would reduce the drastic side effects from anti-rejection drugs. Read more at Transplant Update. For now you will receive therapy for rejection as explained below.

New treatments for acute rejection are also emerging. One is photopheresis. See this page and this page for more about this light-based therapy. It's interesting reading. :-)

 Risk of heart rejection is highest right after transplant surgery. In one study, the first year after transplant 37% of patients had no rejection episodes, 40% had one episode, and 23% had more than one episode. This is why induction therapy is used. Induction therapy is the use of OKT-3 or other heavy-duty drugs to really max out your anti-rejection treatment right after your transplant surgery.
     You will keep taking some anti-rejection drugs for the rest of your life. Further down the page, I explain the actual physical rejection process in 3 versions - short, medium, long. First, I give the info you're most likely to want - how rejection is rated and treated.

There are different kinds of organ rejection but everything on this page is geared toward "acute cellular" rejection. Eighty-five percent of rejection espisodes are of this type. Here is a brief outline of other rejection types:

Chronic rejection
takes place over time - sometimes years after transplant - rather than in acute episodes. It may occur partly from repeated episodes of acute rejection, as well as for other causes not understood. There is no known successful treatment and eventually the donor organ is lost, meaning re-transplant or death
Acute vascular or humoral rejection
carries a much higher risk of death, transplant CAD, and poor long-term survival than acute cellular rejection. About 18% of heart recipients have this pattern of rejection and they have a one-year survival of 67% and a 5-year survival of 36%. These patients are 8 times more likely than others to lose their donor heart. Humoral rejection is more likely in women and in patients with positive cross matches.
Mixed rejection
a heart recipient may - and often does - have some acute cellular rejection and some acute vascular rejection at the same time
Hyperacute rejection
is very rare and usually only happens immediately after transplant. No successful treatment for it is known, and it is fatal in minutes to hours
Acute Organ Rejection - ISHLT Grades and Treatment
 Grade   Patients Status   Early (less than 3 months)   Late (after 3 months) 
 0 Stable No changes Standard immunosuppression
 1A Stable No changes Standard immunosuppression
 1B Stable No changes Adjust drug doses
 2 Stable No changes Adjust drug doses
 2 Unstable, meaning:
rising CVP and PCWP, decreasing EF
arrhythmias and other symptoms
Increase drug doses
possibly add 100mg prednisone TID
Same as for early treatment
 3A Stable Increase drug doses
100mg prednisone TID
Same as for early treatment
 3A Unstable, meaning:
rising CVP and PCWP, decreasing EF
arrhythmias and other symptoms
one gram IV prednisone
Increase drug doses
Same as for early treatment
 3B Stable one gram IV prednisone
Increase drug doses
100mg oral prednisone TID
 3B Unstable, meaning:
rising CVP and PCWP, decreasing EF
arrhythmias and other symptoms
ALG, ATG, or OKT3 for 7 to 10 days one gram IV prednisone for 3 days
 4 Irrelevant ALG, ATG, or OKT3 for 7 to 10 days  

Patients with mild rejection usually take oral prednisone. If they are also having heart function problems, they may get "pulse methylprednisolone" - IV steroids - once a day for for 3 to 5 days. This works about 50 to 60% of the time. If that does not do it, you are said to have "steroid resistant rejection."
     In that case, you'll probably get monoclonal or polyclonal antibodies - OKT3, ALG, ATG. You can think of these as anti-T-cell antibodies, which bind to, and destroy, your T-cells. There are 2 more recently approved monoclonal antibody treatments: daclizumab (Zenapax) and basiliximab (Simulect).


The Immune System & Rejection 
short version

The immune system recognizes as foreign and attacks anything different from your normal body tissues. Even substances that are only a little bit different, like a transplanted human heart, are considered foreign invaders.
     When an organ is transplanted, a small part of the donor organ is recognized as foreign and your immune system attacks it. To lower the chances of transplant rejection, donors who share as many MHC genes as possible with the transplant recipient are preferred. Even then, most transplant recipients are given lots of drugs to suppress their immune response and prevent organ rejection.
     If the transplanted tissue contains T-cells from the donor, these donor T-cells may recognize the recipient's tissue as foreign and attack them. This can be fatal and is called graft-versus-host (GVH) disease. This is prevented as much as possible by trying to remove all donor T-cells from the donor organ before transplant takes place.

The Immune System & Rejection
medium version

By 1863, Paul Bert had shown that tissues transplanted from one person to another are rejected. Forty years later, Carl Jensen proved that this rejection was carried out by the immune system.
     To do its job, your immune system must know what is an invader and what isn't. This recognition system uses markers called histocompatibility antigens. These antigens are found on the surface of every cell in your body. The immune system attacks anything without the proper identifyers. "Unrecognized" antigens include those on invading viruses and bacteria. Your immune system has no way to tell if tissue is harmful or not, just if it is different. Your "new" heart is different as far as your immune system is concerned, so it's got to go!
     In 1958, Jean Dausset discovered the histocompatibility system for "matching" tissue types. The ability to reduce histocompatibility differences is one of the things that makes heart transplants possible. The usual name for this "matching" is HLA or "Human Leukocyte Antigen" matching.
     There are over 200 different histocompatibility antigens. Each person has a certain "set." The odds that 2 unrelated people will have the same set are about one in 30,000. Transplant coordinators try to match histocompatibility antigens of the donor and the recipient as well as possible to minimize rejection. You are part of a "match" program through UNOS, but due to the very short life of a heart outside a body, exact cross-matching for heart transplant is done after surgery has begun and only helps decide how strong your anti-rejection therapy will be. The match is never exact, so you must take drugs to suppress your immune system's response.

The first drugs used for this were azathioprine and prednisone. Those drugs suppress the entire immune system, leaving you wide open to infections and cancer. They also have some very nasty side effects.
     The next breakthrough was cyclosporine, which comes from fungus found in dirt from a certain area. Cyclosporine suppresses the part of the immune system involved in organ rejection without suppressing the entire system completely. This allows you to prevent rejection without being quite as vulnerable to infections.
     A few years later, another fungus product, tacrolimus (FK-506 or Prograf), was found that is even better for kidney, liver, heart, and lung transplants. However, patients who take these drugs still face increased risk of infection and cancer, and the drugs can cause kidney damage. A combination of immune-suppressing drugs is used to try to prevent severe side effects.
     It was not until cyclosporine was approved for use in the United States in 1983 that heart transplants gained widespread use. Now, about 83% of heart recipients survive the first year.

The Immune System & Rejection
long version

There are 2 kinds of immunity: innate and adaptive. Innate immunity is the body's first line of defense. Innate immunity is provided by barriers like skin, tears, mucus, and saliva, as well as by rapid inflammation of tissues. As a woodworker, I can vouch that this inflammation will actually push foreign objects like splinters out of your skin all on its own.
     If an invader gets past this first line of defense, your immune system makes a customized defense. Your immune system can call upon this defense later if the same invader attacks again. This is called adaptive immunity and it has 4 characteristics:

  1. It responds only after an invader invades
  2. It is specific, tailoring each response to act only on a specific kind of invader
  3. It has memory, responding better to later attacks by an invader, even if the second attack is years later
  4. It does not usually attack normal body components, only those substances it recognizes as non-self

Immune responses are actually reactions to structures on the surface of invading organisms called antigens. There are 2 kinds of immune responses:

During humoral immune response, proteins called antibodies appear in the blood and other bodily fluids. Antibodies can stick to - and destroy - antigens. Humoral immune responses attack invaders that act outside of cells, like bacteria and poisons
These immune responses can destroy cells. Their destructive activity is limited to cells that are either infected with, or producing, a certain antigen. A cell-mediated response attacks invaders that reproduce inside cells, like viruses. Cell-mediated responses may also destroy cells making improper structures, like some cancers

Humoral immune response White blood cells are the mainstay of the immune system. Some white blood cells, called macrophages, surround and "eat" invading bacteria. Macrophages can also attach to invading antigens and deliver them to other parts of the immune system to be destroyed.
     Lymphocytes are specialized white blood cells which identify and destroy invading antigens. All lymphocytes begin as "stem cells" in your bone marrow, but they mature in 2 different places. Some lymphocytes mature in the bone marrow and are called B-lymphocytes. B-lymphocytes make antibodies which circulate through bodily fluids, sticking to antigens and destroying them.
     Other lymphocytes called T-lymphocytes or T-cells mature in the thymus, a small organ behind the breastbone. Some T-cells called cytotoxic or "killer T-cells" directly destroy cells that have certain antigens on their surface.
     "Helper T-cells" regulate the immune system by controlling the strength of immune responses. Lymphocytes constantly travel throughout the blood, looking for invaders.
     Each immune response is tailored to a specific kind of invading antigen. Each lymphocyte has an antigen receptor - a structure on its surface - that can bind to a matching structure on the antigen, like a lock and key. Although lymphocytes can make billions of different kinds of antigen receptors, each individual lymphocyte makes only one.
     When an antigen enters a body cell, transporter molecules inside the cell attach themselves to the antigen and transport it to the cell's surface, where the antigen is caught by a T-cell. These transport molecules are made by a group of genes called the major histocompatibility complex (MHC) and are therefore known as "MHC molecules." The humoral immune response works something like this:

  1. Invader antigens enter the body
  2. Macrophages take up some of the antigen and attach it to class 2 MHC molecules
  3. The MHC molecules give the antigen to T-helper cells
  4. The T-helper cells bind the presented antigen, which stimulates the T-helper cells to divide and secrete molecules called interleukins
  5. The interleukins activate any B-cells that have also bound the antigen
  6. The activated B-cells divide and secrete antibodies
  7. The secreted antibodies bind the antigen and destroy it
  8. End of taht particular invader

The antibodies from step 6 and 7 are Y-shaped proteins called immunoglobulins (Ig) and are only made by B-cells. The antibody binds to the antigen at the ends of the arms of the Y. The base of the Y decides how the antibody will destroy the antigen. This area classifies antibodies into 5 classes: IgM, IgG, IgA, IgD, and IgE. Which Ig classes a B-cell makes depends on the kind of interleukins it gets from the T-helper cells.
     Antibodies may be able to stop the harmful effects of an antigen simply by binding to it (neutralizing it), which may stop it from causing any further harm. All classes of antibodies can neutralize antigens. Antibodies also help destroy antigens by getting them ready to be eaten by macrophages. The antibodies coat the surface of antigens. Antigens coated with antibodies are more likely to stick to a macrophage and be eaten.
Cell-mediated immune response As with humoral immune response, this involves a complex chain of events after antigens enter the body. Helper T-cells are required, which bind the antigen and are thereby activated to divide and produce interleukins. The interleukins activate killer T-cells.

Material taken from various sources, including Microsoft's Encyclopedia Encarta - Updated June 3, 2002

All information on this site is opinion only. All concepts, explanations, trials, and studies have been re-written in plain English and may contain errors. I am not a doctor. Use the reference information at the end of each article to search MedLine for more complete and accurate information. All original copyrights apply. No information on this page should be used by any person to affect their medical, legal, educational, social, or psychological treatment in any way. I am not a doctor. This web site and all its pages, graphics, and content copyright © 1997, 1998, 1999, 2000, 2001, 2002, 2003, 2004 Jon C.

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