Overview Transplant

Grafts may be the patient’s own tissue (autograft, z., Bone, bone marrow, and skin transplants) genetically identical (syngenic [between identical twins]) donor tissue (isografts) genetically dissimilar donor tissue (allograft or homograft) Rare transplants from another species (xenografts or straight grafts) transplanted tissue may be, the cells (as in hematopoietic stem cells [HSC], lymphocytes, and pancreatic islet cell transplants) parts or segments of an organ (such as pulmonary lobar transplants and skin grafts) whole organs (such as heart or kidney transplantation) ‘fabric (z. B. composite tissue grafts) is transmitted to a graft anatomically normal position is referred to as heterotopic transmission (eg. as in a transplant Sp forming kidney in the iliac fossa of the receiver). A transplant is almost always carried out to improve the survival of patients. However, some methods (eg. B. Hand, larynx, tongue and face transplant) increase the quality of life but do not improve survival and may involve in the operation and because of the immunosuppression considerable risks. These techniques are in early experimental stage (tissue transplantation). With rare exceptions transplants are Allografttransplantationen from living related and unrelated persons or from deceased donors. For kidney and HSC transplants from living donors are mainly used; less frequently for liver, pancreas and lung segments. Nevertheless, the organ demand exceeds the supply of available organs by far, and so the number of patients waiting for an organ transplant is growing. The use of organ transplants from deceased donors (from brain-dead donors with beating yet or no longer beating heart) has helped to reduce the discrepancy between organ demand and supply. Transplant rejection and graft-versus-host disease in all recipients of an allograft is a risk of rejection because the recipient’s immune system recognizes the graft as foreign and tries to destroy it. Receiver of immune cells (especially bone marrow, intestine and liver) the risk of a graft versus host reaction (graft-versus-host-disease = GVHD) have cancer. With a screening before transplantation and immunosuppression during and after transplantation, these complications can be minimized. Organ allocation for some organs (liver, heart) the assignment of the severity of disease and the waiting time of the receiver, or both is crucial depends, while for the allocation of other organs (kidney, lung, intestine) next to the disease severity. In the US and Puerto Rico organs are initially assigned 12 geographic regions and distributed among local organ donor organizations. If there are no receivers in the first region and the institutions receivers are allocated in other regions. (N. D. Talk .: In Europe, patients waiting for a transplant, performed on a list in Euro Transplant Center in Leiden [Netherlands].) Euro Transplant coordinate available donor organs in response to tissue compatibility and priority status for waiting patients. In Germany, the German Organ Transplantation Foundation (DSO) for the organization of organ transplantation is responsible. Pretransplantations screening Before took the risk to the cost of a transplant and the scarce donor organs are distributed, medical teams examine the potential recipients for medical and non-medical factors that may affect the likelihood of success. Histocompatibility When Pretransplantationsscreening recipient and donor are tested for human leukocyte antigens (HLAs, including major histocompatibility complexes called [MHC]) ABO antigens receiver is tested for presensitization to donor antigens The typing of HLA tissue extremely important for the following: kidney The most common types HSC transplantation the urgency of the transplantation of these organs is typically large, often before a HLA tissue typing can be completed. Heart Liver Pancreas Lung HLA tissue typing of peripheral blood or lymph node lymphocytes is performed to find a match of the most important known Histokompatibilitätsdeterminanten of donor and recipient. More than 1250 alleles determine six HLA-antigens (HLA-A, -B, -C, -DP, -DQ, -DR), which makes the correspondence to a challenge; in the US, for example, agree on average, only two out of six antigens of kidney donors and recipients agree. The correspondence of the greatest possible number of HLA antigens significantly improves the functional survival of transplants of living related kidney and HSC-donors; the compliance of live transplants of HLA-unrelated donors improves survival, albeit due to still many undiscovered Histokompatibilitätsunterschiede less successful. Improved immunotherapy has expanded the suitability for transplantation, and patients will no longer automatically excluded from a transplant because of HLA incompatibilities. the AB0 compatibility and HLA compatibility are important for the survival of transplants. Not matching AB0 antigens can hyperacute rejection of vascular grafts (eg. As kidney, heart), the AB0 antigens on the endothelial surface of the cell membranes have cause. A presensitization against HLA and AB0 antigens can start from a previous contact with donor antigens by blood transfusions, transplants or pregnancies. You can using serological tests or more frequently detected in a cytotoxicity recipient serum and donor lymphocytes in the presence of complement. A positive cross indicates the presence of antibodies in the recipient’s serum which are directed against AB0 or ??class I HLA antigens of the donor; this is considered an absolute contraindication for transplantation, except perhaps in young children (up to 14 months), which have not yet formed isohemagglutinins. High-dose iv Doses of immunoglobulin (Ig) and plasma exchange have been used as immunosuppressive therapy of HLA-antibodies, if a more compatible donor organ is not available. The costs are high, but medium-term results are encouraging and seem to those of sensitized patients to be similar. Even a negative crossmatch is not a guarantee of safety; on compatible but not identical AB0 antigens (z. B. donor receiver 0 and A, B or AB) is the hemolysis potential complication due to the antibody production by transplanted (passenger) donor lymphocytes. Although a match of HLA and ABO antigens generally improved graft survival, white patients are not disadvantaged because Organ donation is less common among non-whites, and therefore the number of potential non-white donors is limited. Stage renal disease is more common in blacks, and thus the need for organs is greater. Non-white patients may have different HLA polymorphisms from white donors, a higher rate of presensitization to HLA antigens and a higher incidence of blood groups 0 and B. contagion Exposure of donor and recipient against common infectious agents and active and latent infections have before transplantation are found to minimize the risk of transmission of infection of the donor and the risk of deterioration or reactivation of an existing infection at the receiver (because use of immunosuppressive drugs). The screening usually comprises the prehistory and tests for cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), varicella zoster virus (VZV), HIV, hepatitis B and C virus, HIV, West Nile virus, as well as a Mycobacterium tuberculosis (TB) test (if exposure is suspected) is performed. Positive results can make an anti-viral therapy (for. Example, in infections with CMV or hepatitis B) after transplantation necessary or constitute a contraindication for transplantation until the infection is controlled (eg. As in the detection of HIV with AIDS). Contraindications to transplantation of the absolute contraindications of transplantation include: Active infection unless the infection is at the receiver on the organ confined, to be replaced (. eg liver abscesses) cancer (except for hepatocellular carcinoma, which is confined to the liver and specific neuroendocrine tumors at the receiver) A positive-checks, which was identified by lymphocytotoxic tests. Among the relative contraindications include the following: age> 65 Poor functional or nutritional condition (including severe obesity) HIV infection multi-organ failure Psychological and social factors also play an important role in the success of transplantation. So drug-addicted or mentally unstable people will be less compliant in meeting the need lifelong treatment regimens and follow-up probably. The criteria for the selection of patients with relative contraindications differ in the medical centers. Immunosuppressants are well tolerated and effective in HIV-positive transplant patients. Immunosuppression after transplantation immunosuppressive drugs are used to keep rejection reactions under control and are primarily responsible for the success of transplantation. However, because they suppress all immunologic reactions, they contribute to many complications after transplantation, including the development of cancer, acceleration of cardiovascular disease and even death due to excessively many infections. The immunosuppressive therapy usually has to be maintained long after the transplant. The initially administered high doses can be reduced a few weeks after the transplant. With lower doses can be continued indefinitely if it does not lead to rejection. The further reduction in immunosuppressive doses for a prolonged period after transplantation and study protocols for increasing the tolerance of donor organs are under consideration. Corticosteroids Corticosteroids are administered at the time of transplantation generally high doses. Then they will be gradually reduced to the maintenance dose to be continued indefinitely. Several months after transplantation Corticosteroids may be administered every two days; This process helps to prevent growth impairment in children. Should be a rejection, high doses are given again. Regimens in which corticosteroids can be reduced (steroid savings schemes) are Entwicklung.Calcineurininhibitoren These drugs (cyclosporine, tacrolimus) block T-cell transcription processes that are necessary for the production of cytokines by selectively T- cell proliferation and activation inhibit. Ciclosporinist the drug most commonly used in heart and lung transplants. It can be administered alone, but usually is used in combination with other drugs (eg. As azathioprine, prednisone), so that lower, less toxic doses can be given. The initial dose is reduced to a maintenance dose shortly after transplantation. Cyclosporine is metabolized by the cytochrome P450-3A enzyme, while other drugs will affect the blood levels. As a serious dose-related adverse side effect of cyclosporine nephrotoxicity may occur. Cyclosporine causes vasoconstriction of the afferent (preglomerular) arterioles, resulting in damage to the glomerular apparatus and glomerular hypoperfusion and finally ends with chronic renal failure. B-cell lymphoma and lymphoproliferative polyclonal B-cell disorders may be associated with EBV. They have been observed more frequently in patients receiving high doses of cyclosporin, or combinations of cyclosporine with other directed against T-cell immunosuppressive drugs. In addition to less severe side effects (eg. As gingival hyperplasia, hirsutism, hypertrichosis) may occur adverse effects such as diabetes, hepatotoxicity, node gout, refractory hypertension, neurotoxicity (including tremors) and increased incidence of other tumors. Serum levels of cyclosporine are not correlated with its efficacy or its toxic effects. Tacrolimusist the immunosuppressant most widely used for kidney, liver, pancreas or small bowel transplantation. Tacrolimus can be given at the time of transplantation or until days later. The dosage should be determined by blood levels that are influenced as for cyclosporine, drug interactions. Treatment with tacrolimus may be useful if cyclosporine is ineffective or has intolerable side effects. The side effects of tacrolimus correspond approximately to those of cyclosporine, tacrolimus except that rather tends to induce diabetes while gingival hyperplasia and hirsutism occur less frequently. Lymphoproliferative disorders appear in patients receiving tacrolimus are taking to occur more often, even a few weeks after the transplant, and improve, partially or completely, if the drug is discontinued. If lymphoproliferative disorders occur tacrolimus should be discontinued and cyclosporine or other immunosuppressive drugs should werden.Purinmetabolismusinhibitoren replaced Examples are azathioprine and mycophenolate mofetil (MMF). Azathioprine, an antimetabolite, is typically administered from the time of transplantation. It is well tolerated by most patients indefinitely. The most serious side effects include bone marrow depression and, in rare cases, hepatitis. Systemic hypersensitivity reactions show> 5% of patients. Azathioprine is often administered in combination with low-dose calcineurin inhibitors. Mycophenolate mofetil (MMF), a prodrug which is metabolized to mycophenolic acid, causes a reversible inhibition of inosine monophosphate dehydrogenase. The inosine monophosphate dehydrogenase, an enzyme of the guanine nucleotide-path, which limits the rate of lymphocyte proliferation. Patients with kidney, heart or liver transplant obtained MMF in combination with cyclosporin (or tacrolimus) and corticosteroids. The most common side effects include leukopenia, nausea, vomiting and Diarrhoe.Rapamycine These drugs (sirolimus and everolimus) block a very important regulatory kinase (mammalian target of rapamycin [mTOR]) in lymphocytes, suggesting a cell cycle arrest and inhibition of lymphocyte reaction a cytokine stimulation leads. Sirolimus is usually administered in combination with cyclosporine and corticosteroids and has proven itself in patients with renal insufficiency. The undesirable side effects include hyperlipidemia, interstitial pneumonia, leg edema, impaired wound healing and bone marrow suppression with leucopenia, thrombocytopenia and anemia. Everolimus is used to prevent kidney and liver transplant rejection. The undesirable side effects similar to those of immunoglobulins Sirolimus.Immunsuppressive examples are anti-lymphocyte globulin (ALG) thymocyte globulin (ATG) Both are fractions of animal antisera directed against human cells: lymphocytes (ALG) and thymus cells (ATG). ALG and ATG suppress cellular immunity while the humoral remains intact. They are administered in combination with other immunosuppressive and can therefore be applied in lower and less toxic doses. The control of acute episodes of rejection reactions by ALG and ATG improved survival of transplants; their administration at the time of transplantation may reduce the incidence of rejection and allows subsequent therapy with calcineurin inhibitors, whereby the toxicity is reduced. The application of thoroughly purified serum fractions in the occurrence of adverse side effects (eg., Anaphylaxis, serum sickness, and antigen-antibody-induced glomerulonephritis) considerably verringert.Monoklonale Antibodies Monoclonal antibodies (mAbs) directed against T-cells, provide a higher concentration of anti-T-cell antibodies and fewer irrelevant serum proteins than ALG and ATG. OKT3 (a mouse antibody) inhibits the T-cell antigen receptor (TCR) and thereby leads to immunosuppression. It is used primarily to control acute rejection episodes was but also applied at the time of transplantation to reduce the incidence of rejection crises or delay its onset. However, the drug is no longer available. Monoclonal antibodies with anti-IL-2 receptor inhibit T cell proliferation by blocking the effect of the secreted by activated T-cells IL-2. At the time of transplantation, they are used in addition as a supportive immunosuppressants. Basiliximab, which is a humanized anti-IL-2 receptor antibody, is increasingly in the treatment of acute rejection of kidney, liver and small intestine transplants are used. At the time of transplantation, it is also used as a supporting immunosuppressant. The only previously reported adverse reaction is anaphylaxis, but an increased risk of lymphoproliferative diseases can werden.Bestrahlung not excluded grafts, local tissue of the recipient or both can be exposed to rejection treatment of kidney transplant when other therapeutic regimens (eg. As corticosteroids and ATG) are invalid. The application of total lymphoid irradiation is still in the experimental stage, even if it seems that they suppress cellular immunity safe by the suppressor T cells are stimulated first and later may take place clonal deletion of specific Ag-reactive cells. However, as immunosuppressants are now so effective, the need for therapeutic approaches Bestrahlung.Zukünftige falls currently searching for protocols and agents that induce antigen specific graft tolerance without suppressing other immune responses. Two strategies are promising: Blockade of T-cell costimulatory pathways to a cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) IgG1 fusion protein induction of chimeras (coexistence of immune cells of the donor and recipient, in which graft tissue as “self” is recognized). Here, the transplant goes myeloablative treatment ahead (eg. As with Ciclophosphamid, irradiation of the thymus, ATG and cyclosporine), the transient T-cell depletion, the implantation of donor HSC and subsequently the tolerance solid organ transplants of the same should induce donor (is currently under investigation). Belatacept, another antibody that inhibits T-cell costimulatory pathways, can be used in renal transplant recipients. However, the incidence of progressive multifocal leukoencephalopathy, a fatal CNS disease seems, and the incidence of viral infections increased. Lymphoproliferative after transplantation is another problem. Immunosuppressive drugs for the treatment of transplant rejection immunosuppressive mechanism of action indication most important adverse effects antilymphocyte globulin (ALG) antithymocyte globulin (ATG) inhibition of lymphocyte (ALG) or thymic cells (ATG) induction, long-term and acute treatment of rejection anaphylaxis , serum sickness, antigen-antibody-induced glomerulonephritis Azathioprine inhibitors of purine metabolism long-term therapy, myelosuppression, Hepatitis Basiliximab inhibition of T cell proliferation by blocking the action of IL-2 In most cases, induction of infection, anaphylaxis, myeloproliferative diseases belatacept antibodies, T-cell costimulatory pathways inhibit long-term therapy Progressive multifocal leukoencephalopathy or other viral infectionsCorticosteroid anti-inflammatory induction, long-term and supportive treatment of acute rejection diabetes, hypertension, osteoporosis, atherosclerosis cyclosporin calcineurin inhibition (blocking T-cell transcription) induction (rare), long-term treatment and treatment of acute and chronic rejection nephrotoxicity, neurotoxicity, hyperlipidemia, hirsutism, hypertrichosis, diabetes, hepatotoxicity, Tophusgicht, refractory hypertension, increased incidence of other tumors, gingival hypertrophy everolimus, sirolimus Inhibition of mTOR inhibition of lymphocyte response to Zytokinstimulierung long-term therapy Interstitial pneumonia, leg edema, hyperlipidemia, impaired wound healing, bone marrow depression mycophenolate inhibitors of purine metabolism long-term therapy, myelosuppression, nausea, vomiting, diarrhea tacrolimus calcineurin inhibition (blockage of the T cell transcription) induction, long-term treatment and treatment of acute and chronic rejection nephrotoxicity Neuroto xizität, hyperlipidemia, alopecia, hypertension mTOR = mammalian target of rapamycin post-transplant complications include complications: infection rejection renal cancer atherosclerosis rejection The rejection of a solid organ can hyper acute, accelerated, acute or chronic (late rejection). These categories can be distinguished histologically and approximately by the time of occurrence. Symptoms vary depending on the affected organ (see table: manifestations of graft rejection by category). Hyperacute rejection has the following characteristics: caused by pre-existing antibodies complement-kick is within 48 hours after the transplant for you, which are directed against graft antigens (presensitization). It is characterized by thrombosis in small vessels and graft infarction The hyperacute rejection has become rare with 1% of cases due to improved screening before transplantation. The only effective treatment is removal of the graft. Accelerated rejection has the following properties: If 3 to 5 days after the transplantation Caused by graft antigens directed against existing complement-antibodies. Histopathological examination reveals cellular infiltrates with or without vascular changes. The accelerated rejection reaction rarely occurs. The treatment consists in the administration of high-dose corticosteroids (steroid pulse therapy), or – in the event of vascular changes – antilymphocyte preparations. Plasma exchange for faster removal of circulating antibodies has been applied with some success. Acute rejection is graft destruction after the transplant and has the following characteristics: Occurs later, about 5 days after transplantation (because unlike the hyper acute and accelerated rejection, acute rejection by a de novo anti-graft T cell response is mediated, not caused by a T cell-mediated delayed hypersensitivity reaction to histocompatibility antigens of the allograft by existing antibodies). Is characterized by mononuclear cell infiltration, with varying degrees of hemorrhage, edema and necrosis, but with vascular integrity, which is usually maintained (although vascular endothelium appears to be a primary target) Acute rejection is blamed for about half of all rejection crises, which occur within 10 years after transplantation. With increased immunosuppressive therapy (eg. B. steroid pulse therapy, ALG, or both) can be often overcome acute rejection reaction. After overcoming the rejection badly damaged elements of the graft heal fibrotic, while the rest of the graft is functioning normally. Although the immunosuppressive drugs are reduced to very low doses, the allograft survives for long periods. The chronic type of transplant rejection is a delay in graft destruction, which often occurs without fever. It has all of the following: If typically until months or years after the transplant, but occasionally can occur within a few weeks. The causes are varied and include early antibody-mediated rejection, periprocedural ischemic and injuries by repeated perfusions, drug toxicity, infections and vascular factors (eg. As hypertension, hyperlipidemia). Is pathologically characterized by proliferation of a new intima, that consists of smooth muscle cells and extracellular matrix (transplant atherosclerosis) which gradually occlude the vessel lumen. It remains a fibrotic graft ischemic spots About half of the other episodes of rejection is due to chronic rejection reactions. Despite immunosuppressive therapy of chronic type of transplant rejection proceeds slowly; an established therapy yet exists. There are reports that in some patients chronic liver rejection can be controlled with tacrolimus. Manifestationen der Transplantatabstoßung nach Kategorie Organ Hyperakut Beschleunigt Akuttherapie Chronisch Nieren Fieber, Anurie Fieber, Oligurie, Schwellung und Empfindlichkeit des Transplantats Fieber, erhöhtes Serum-Kreatinin, Bluthochdruck, Gewichtszunahme, Schwellung und Empfindlichkeit des Transplantats Proteine, Lymphozyten und Nierentubuluszellen im Urin-Sediment Proteinurie mit oder ohne Bluthochdruck, nephrotisches Syndrom Leber Fieber, stark erhöhte Leberwerte (AST, Bilirubin), Koagulopathie Fieber, Gerinnungsstörung, stark erhöhte Leberwerte (AST, Bilirubin), Aszites Anorexie, Schmerzen, Fieber, Gelbsucht, leicht (Ton)-gefärbter Stuhl, dunkler Urin, erhöhte Leberwerte (AST, Bilirubin) Gelbsucht, verschwindendes Gallengangssyndrom (mit erhöhtem Bilirubin, alkalische Phosphatase und GGT), leicht erhöhter Leberwerte (AST, Bilirubin), Aszites Herz* Kardiogener Schock Vorhofarrhythmie, kardiogener Schock Herzinsuffizienz, Vorhofarrhythmie Atemnot bei Anstrengung, geringe Stresstoleranz Lunge Schlechte Sauerstoffversorgung, Fieber, Husten, Atemnot, verminderte FEV1 Schlechte Sauerstoffversorgung, Fieber, Husten, Dyspnoe, im Röntgenbild: Brusti