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Transplantation of tissues and whole organs has become commonplace. Transplantation is useful for treating a variety of disease conditions not amenable to other therapies. The technical aspects of tissue and organ harvesting are well-understood, and the surgical procedures for grafting tissues and organs into the body are also well-documented and reliable. However, the major problems that limit the usefulness of transplantation include:
Shortages of available tissues and organs
Immunologic rejection phenomena
Transplantation can be categorized by the source of the tissues and organs obtained:
Autogenous grafts: these are tissues taken from one part of the body and placed in another part in the same person. Since the tissues come from the same person, there is no problem with rejection. Examples include:
Autogenous vein coronary bypass grafting: Persons with severe occlusive coronary atherosclerosis can be treated with grafting of new vessels into the heart to bypass the occluded vessels. Most commonly, portions of the saphenous vein from the leg are harvested and utilized as grafts. The internal mammary arteries from chest wall can also be re-routed to the heart. Radial artery from the forearm can also be harvested for such use.
Skin grafting: Persons who have suffered superficial burn injuries to the skin that are full thickness require grafting of new skin. The skin can be harvested by taking a partial thickness of skin from a site that has not been burned (such as thighs or torso) and grafting it to the burned site(s).
Bone marrow: Persons with malignancies that are amenable to highly toxic chemotherapy can have marrow (or stem cells) harvested prior to chemotherapy. The harvested tissues are treated to try and remove any malignant cells. After the chemotherapy is given, the patient is "rescued" from the toxic effects, which typically destroy marrow, by re-introducing the previously harvested marrow or stem cells.
Hair: In persons desiring a cosmetic solution to aging with pattern baldness of the scalp, plugs of skin with hair follicles can be transplanted from a hair-bearing area of skin to the scalp.
Allogeneic grafts: Allografts are tissues and organs taken from one person and grafted into another person (within the human species). The grafts may come from donors who are living and related, living but unrelated, or from cadavers (persons who have died). The only situation in which virtually complete immune tolerance is achieved is when such grafts occur between identical twins. For all other persons, the immunologic differences present potential problems with rejection of the grafts.
There are situations in which the grafts present little threat of immunologic rejection. These situations arise when the tissues are relatively acellular and express antigens minimally, if at all. Use of these tissues requires no special matching procedures. Such tissues include:
For most whole organ transplants, there is a potential for immunologic rejection. The nature of the potential rejection varies depending upon how antigens are expressed upon the cells composing the organs. The major transplanted organs affected by this limitation are:
Xenografts: Tissues can be transplanted from other species, but there are major problems with immunologic incompatibility. Experimental procedures have employed primates and pigs. It is theoretically possible to breed animals that have a genetic constitution that makes their tissues more compatible with humans. One situation in which a xenograft is commonly employed is the use of a porcine heart valve to replace a failing human heart valve. The porcine valve is treated to make it immunologically inert and mechanically stable, and it functions well.
Fetal tissue grafts: Fetal tissues have a distinct advantage in transplantation because they are immunologically immature, not having reached a state where they recognize other tissues as "foreign". Thus, they offer the potential for providing a graft without the need to worry about immunologic rejection. A problem with this type of transplantation centers on ethical dilemmas in obtaining and using such tissues.
Human tissues express antigens. These antigens are on their surfaces and within them. The most important of these in transplantation are the antigens associated with the major histocompatibility complex (MHC). These are best known as "HLA" antigens because they were first described on white blood cells (human leukocyte antigens). The genes for the MHC reside on the short arm of chromosome 6 in humans. Each person inherits one gene from each parent to determine the pairs of loci that are present. The purpose of the antigens coded by the genes of the MHC is to bind peptide fragments of foreign proteins (such as proteins from infectious agents) to present to antigen-specific T-lymphocytes. There are three major gene products of the MHC:
Class I antigens: these are antigens expressed on all nucleated cells and on circulating platelets. The loci are designated as HLA-A, HLA-B, and HLA-C. The antigens bind peptides within cells (typically from viruses that proliferate intracellularly) that are presented to cytotoxic CD8-lymphocytes.
Class II antigens: these are antigens have a limited distribution and are seen mainly on B-lymphocytes, activated T-lymphocytes, monocytes, macrophages, endothelial cells, Langerhans cells, renal epithelial cells, and pancreatic beta cells. The loci are designated DR, DP, and DQ. They bind peptides that are derived from exogenous antigens (such as from extracellular bacterial infections) and present them to CD4-lymphocytes.
Class III components: these are the complement components that circulate in the bloodstream.
Transplant rejection can involve both class I and class II HLA antigens. Transplanted tissues that express HLA class I antigens can elicit a cytotoxic CD8-cell response in which there is a hypersensitivity reaction (type II) with direct cytolysis of the cells of the graft. Those tissues expressing HLA class II antigens can provoke a CD4-cell response in which there is a delayed (type IV) hypersensitivity reaction with cytokine activation of macrophages that attack the graft. These two forms of rejection are "cell-mediated". In addition, rejection can also occur when B-cells produce circulating antibodies that attack the graft (type III hypersensitivity, antibody-mediated).
In addition to HLA antigens, there are blood group antigens expressed on red blood cells. These antigens may also be strongly expressed on endothelial cells, particularly in kidney. Thus, ABO matching is particularly important in renal allografts.
Prevention of immunologic rejection takes two forms:
Pharmacologic (immunosuppressive) therapy
The success of allografts such as kidney and marrow depend heavily upon tissue typing for matching of HLA antigens between donor and recipient, because these tissues express HLA antigens to a great degree. Other organs such as heart and liver express such antigens to a lesser degree, so that organ size and availability are more important considerations. For all transplants in which immunologic rejection is a consideration, the long-term use of pharmacologic therapy is important.
Immunosuppressive therapy can increase graft survival, but creates additional problems because the immune system is altered. The drug cyclosporine, which inhibits T-cell mediated immunity by inhibiting cytokine activation (particularly interleukin-2), has revolutionized transplantation. In addition, anti-lymphocyte antibody therapy, as with OKT3, will help to prevent rejection. Corticosteroids and other drugs are also utilized in this manner. In general, immunosuppressive drugs to a better job of preventing cytotoxic or cell-mediated rejection than preventing humoral (antibody-mediated) rejection.
The approximate numbers of major organ transplantation procedures in the U.S. is indicated in the table below:
|Organ||Number of Procedures|
The pathologic complications more specific to the major organ transplantation procedures are given below:
Hyperacute rejection: this rare complication occurs when there are preformed circulating antibodies in the recipient that immediately attack the engrafted kidney. The kidney ceases functioning within minutes. The immunologic lesion is an Arthus reaction with antigen-antibody complexes deposited in vascular walls, complement activation, and neutrophilic infiltration. The extensive vascular injury leads to severe ischemic injury.
Acute rejection: this can occur within days or happen months or years following transplantation. Acute rejection takes two forms:
Acute cellular rejection: Both CD4 and CD8-cells play a role. There is mainly lymphocytic infiltration in a tubulointerstitial distribution.
Acute vascular rejection: circulating antibodies deposit in the walls of renal arteries, resulting in a vasculitis, leading to intimal thickening, lumenal narrowing, and ischemia.
Chronic rejection: this may begin to occur months following transplantation. Both cell-mediated and humoral immunologic mechanisms play a role. It is slowly progressive over months. The injury is mainly vascular, with progressive intimal thickening that results in ongoing ischemia with interstitial fibrosis, tubular atrophy, and glomerular sclerosis.
Cyclosporine nephrotoxicity: immunosuppressive dosages of cyclosporine can injure the renal parenchyma in a pattern similar to acute cellular rejection.
Recurrence of disease: the disease that led to the necessity for transplantation may recur in the graft. The disease most likely to recur is membranoproliferative glomerulonephritis, type II (MPGN II). Other diseases with a significant recurrence risk are IgA nephropathy, MPGN type I, membranous glomerulonephritis, and focal segmental glomerulosclerosis (FSGS). Both diabetic nephropathy and lupus nephritis are unlikely to recur in the allograft.
De novo renal disease: the allograft may develop a renal disease that previously did not exist. The disease most likely to develop is membranous glomerulonephritis.
Preservation injury: this can occur secondary to organ harvesting and tissue preservation. Tubule cell swelling, interstitial edema and leukocyte infiltration can be seen.
Hyperacute rejection: this uncommon event may follow transplantation of liver into ABO incompatible recipients, but it does not occur in all ABO incompatible transplants. Massive hemorrhage and infarction may occur very quickly, or in days to weeks.
Acute cellular rejection: this phenomenon involves lymphocytes that attack the allograft. The major features are portal tract inflammation, bile duct injury, and endotheliitis in portal and central veins. This rejection process can be graded to determine the severity and the type of therapy. Severe rejection leads to "vanishing bile ducts" with fibrotic portal tracts and severe cholestasis.
Chronic rejection: this reaction takes place months to years following transplantation. It is mainly an arteriopathy. Foamy macrophages accumulate in large and small arteries, leading to intimal proliferation, lumenal narrowing, and ischemic changes. This process can be accompanied by bile duct destruction.
Recurrent disease: the most common situation for this complication is transplantation for liver failure from chronic viral hepatitis. Recurrent viral hepatitis in the transplanted liver tends to be more indolent than the original disease involving the native liver, but the histologic findings are similar. Also, transplantation for hepatocellular carcinoma is complicated by recurrence of this neoplasm.
Rejection: both acute vascular and acute cellular rejection phenomena can occur and may be present together or separately in varying degrees of severity. Endomyocardial biopsies are routinely performed on recipients of cardiac transplants to assess rejection and adjust immunosuppressive therapy, especially in the first weeks to months following transplantation. Grading of the severity can aid in determining therapy. With cellular rejection, mononuclear infiltrates are seen in the intersititium along with myocyte necrosis and hemorrhage. Vascular rejection can be identified by appearance of antibody in vascular walls.
Arteriopathy: over time following transplantation, the small distal epicardial and intramyocardial coronary artery branches undergo concentric intimal proliferation. This allograft arteriopathy, which can be considered a form of chronic rejection, leads to progressive lumenal narrowing and widespread ischemic changes. This can occur within months of transplantation, but more typically is progressive over years. After 5 years, over 90% of allografts will demonstrate some degree of arteriopathy.
Acute rejection can occur soon after transplantation. The grade, or severity, of the rejection reaction is based upon the amount of perivascular and interstitial infiltration of mononuclear cells.
Chronic rejection is more insidious and consists mainly of two morphologic alterations. Bronchiolitis obliterans can be seen, and can be divided into active and inactive forms. Vascular sclerosis can also occur and may manifest as accelerated pulmonary arterial atherosclerosis or as venous sclerosis.
Many transplants of whole pancreas are done in conjunction with renal transplantation, since the underlying disease--diabetes mellitus--can involve both organs. Acute rejection can complicate whole organ pancreatic transplantation, and features can include vascular and acinar inflammation and necrosis. Serum amylase and lipase levels may aid in diagnosing graft failure.
Surgical placement of the pancreas to provide drainage (systemic or portal venous drainage; bladder or duodenal exocrine drainage) may determine other potential complications. Pancreatitis and vascular thrombosis are additional complications limiting graft survival.
Graft versus host disease (GVHD): since the marrow itself contains cells (lymphocytes) that are immunocompent, it is possible that these cells in the marrow that engrafts in the host can attack native host cells. Thus, the graft attacks the host. Antigen matching helps to reduce the risk of GVHD. The tissues mainly affected by GVHD are skin, bowel, and liver. The accompanying clinical findings are skin rash, diarrhea, and jaundice. GVHD can occur in the weeks to months following transplantation. A small amount of GVHD may be beneficial in persons treated for malignant disease, in that the newly engrafted lymphoyctes will attack host malignant cells as foreign.
Veno-occlusive disease (VOD): the chemotherapeutic drugs, combined with radiation therapy, that precede bone marrow transplantation can produce tissue injury. In the liver, some chemotherapeutic agents can predispose to venular sclerosis that manifests in the weeks following transplantation with liver disease and jaundice.
Non-engraftment: the transplanted marrow may fail to engraft, or there may be slow engraftment, which leaves the recipient dependent upon blood products and increases the risk for infection.
Recurrence: the original disease, such as a leukemia, may recur following marrow transplantation. The original neoplasm may not have been sufficiently sensitive to the chemotherapy and radiation preparatory to the marrow transplantation.
Post-transplantation lymphoproliferative disorder (PTLD): the immune suppression that is necessary in order to prevent rejection and increase allograft survival may give rise to PTLD. PTLD occurs in <1% of allogeneic bone marrow recipients, 1 to 5% of renal allograft recipients, and in up to 20% of cardiac transplant patients. Patients treated with cyclosporine or OKT3 can have onset of PTLD as early as a month following transplantation. Recipients who were Epstein-Barr virus (EBV) seronegative at the time of transplantation also have an increased risk for PTLD.
A PTLD is typically an extranodal B cell proliferation of host origin associated with Epstein-Barr virus (EBV) infection that does not respond to chemotherapy or radiation. The EBV infection drives the proliferation of lymphoid cells. This proliferation is not a true neoplasm, which is uncontrolled growth, but is related to immunosuppression.
There are several morphologic patterns of PTLD. One pattern of PTLD is just a reactive lymphoid hyperplasia that usually resolves spontaneously. A polymorphic PTLD pattern demonstrates cellular atypia and even invasion, but frequently responds to a reduction in immunosuppressive therapy. A monomorphic PTLD, however, less frequently responds to reduced immunosuppression and is more aggressive. Though this monomorphic form is strictly not a lymphoma, it may on occasion be treated as such.
Malignancies: Patients receiving organ transplants who require long-term immunosuppressive therapy have an increasing risk for each year following transplantation of the allograft for development of malignancies. The risk may be 100 times that for persons without an allograft. These malignancies can include:
Lymphoproliferative disorders (leukemias, non-Hodgkin's lymphomas, and Hodgkin's disease)
Carcinomas, multifocal (particularly cutaneous carcinomas)
Infections: the immunosuppressive therapy required in patients with allografts will diminish normal functioning of the immune system, particularly the cell-mediated aspects of immunity. This increases the risk for infections, particularly opportunistic infections with organisms not commonly seen in immunocompetent persons. However, infections of all varieties are possible in transplant recipients: bacterial, viral, fungal, parasitic.
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