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Therapie mit Immunsuppressiva und Immunmodulatoren
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In the pipeline, there are a number of novel immunosuppressive drugs in preclinical development or in early clinical trials. The major target of new agents are cell-surface molecules important in immune cell interactions (especially the costimulatory pathway), signaling pathways that activate T cells, T-cell proliferation and trafficking and recruitment of immune cells responsible for rejection. The most promising biologic agents include a humanized anti-CD11a (anti-LFA1), humanized anti-B7.1/B7.2, a second-generation CTLA4Ig (LEA29Y) and a humanized antibody to anti-CD45 RB. Inhibitors of T-cell activation and signaling are still in preclinical development. The most interesting inhibitors of T-cell proliferation include inhibitors of the Janus protein tyrosine kinase, JAK3, and FK778, a leflunomide analog. Chemokines play an important role in rejection by virtue of their critical role as regulator of trafficking and activation of lymphocytes. Early trials of FTY720, a synthetic small molecule with functional homology to sphingosine-1 phosphate leading to lymphocyte sequestration, appear very promising; however, enthusiasm for this drug is mitigated by its potential cardiac side-effects. Antagonists to several chemokine receptors, including CCR1, CXCR3 and CCR5, have been shown to be effective in experimental transplantation and are likely to be considered for clinical development.
Considerable economic and health-related costs are associated with the life-long maintenance immunosuppressive therapy required to prevent transplant rejection. Generic medications have the potential of providing equivalent therapeutic efficacy at a lower economic cost. In 2001, the American Society of Transplantation invited experts to review the data and issues associated with the approval and use of generic immunosuppressants. A summary of that meeting is reported here.
The generic medication approval process has been in effect for more than 30 years. All marketed generic cyclosporin formulations have met FDA criteria demonstrating bioequivalence in healthy subjects, and some were also tested in transplant recipients.
Most participants agreed that generic narrow therapeutic index immunosuppressive agents provide adequate de novo immunosuppression in low-risk transplant recipients. However, some participants expressed concern regarding the currently unquantified risk that may be associated with switching immunosuppressive agents under uncontrolled circumstances. There was broad agreement among the participants that generic medications should be clearly labeled and distinguishable from innovator drugs, and that patients should be educated to inform their physicians of any switch to or among generic alternatives. There was also strong support in favor of requiring studies to demonstrate bioequivalence in potentially at-risk patient populations, specifically African-Americans and pediatric patients.
Cytokines are polypeptide mediators which act as communication signals among cells of the immune system as well as among other cells and tissues in the body. They are a heterogeneous and complex group and include interferons, tumor necrosis factor and chemokines. They play a key role in homeostasis and in host defence and are involved in such inflammatory and autoimmune diseases such as rheumatoid arthritis as well as infectious diseases such as HIV infection and septic shock. Modulation of the production and action of cytokines, as well as their exploitation as therapeutic agents, has been the object of intense and competitive research. This book overviews the field of cytokine research and describes the various approaches that have been taken to develop the pharmacology of these novel mediators. The pharmacology of cytokines is an exploding area which is entering the clinical arena. The book, in the framework of the immunobiology of cytokines, examines the interactions with the cytokine system of a variety of compounds ranging from simple synthetic chemicals to biotechnological products. In addition to examining individual agents and approaches, the book examines the pathophysiology of individual body systems and analysis specific contexts for the pathophysiology of these mediators as well as pharmacological approaches for their control.
The mode of immunosuppressive action of tacrolimus (FK506) and cyclosporin A has been elucidated. Both drugs bind to proteins in the cytoplasm to form complexes, which in turn inhibit the phosphatase activity of calcineurin, an important limiting step in the activation of T cells. The association between drug uptake (pharmacokinetics) and enzyme inhibition (pharmacodynamics) is under current investigation. Great variations in the correlation between blood drug levels and enzyme inhibition could indicate that monitoring calcineurin phosphatase activity for treatment might be superior to monitoring blood drug levels.
Many cancers elicit an anti-tumor immune response, which is nevertheless unable to protect the patient. One approach to boost anti-tumor immunity is to target immunostimulatory cytokines to the tumor. Such targeting can be achieved by generating chimeric proteins (immunocytokines) in which the cytokine in question is fused to the C-terminus of a tumor-specific antibody. Immunocytokines containing interleukin-2 (IL-2) have been efficacious in mouse tumor models and have entered clinical trials. Numerous enhancements of immunocytokines are possible, including use of additional stimulatory cytokines, alternate modes of tumor targeting, structural modifications to improve pharmacokinetics, and removal of potentially immunogenic sequences from the fusion protein. In addition, immunocytokines are likely to be efficacious in combination with other therapies, including some forms of chemotherapy and cancer vaccines.
The discovery of granulocyte colony-stimulating factor (G-CSF) and its potential to regulate neutrophil production and function in the inflammatory process has opened an exciting new era for the supportive care of patients with hematological and malignant diseases. Extensive experience has been gained worldwide with G-CSF therapy, and G-CSF is widely employed clinically, primarily because the safety profile appears to be fairly innocuous. A broad consensus has emerged regarding the clinical utility of G-CSF in neutropenic conditions due to chemotherapy. Furthermore, much interest has focused on the use of G-CSF to mobilize CD34+ hematopoietic stem cells from the marrow to the peripheral blood for use in hematopoietic transplantation. The promising results with G-CSF have promoted further studies, e.g., in immunocompetent patients or in granulocyte transfusion therapy. Here, we review the potential clinical role of G-CSF and describe its future perspectives.
Anemia is a frequent clinical feature with adverse prognostic effects in patients with chronic lymphocytic leukemia (CLL). It may complicate CLL at any time during the course of the disease. Different factors concur to the occurrence of anemia in CLL, as in other lymphoproliferative diseases: leukemic bone marrow infiltration, the myelosuppressive effect of chemotherapy and inhibiting cytokines, autoimmune phenomena, hypersplenism, a poor nutritional status that leads to folic acid, vitamin B12 and iron deficiency. In addition, a defective endogenous erythropoietin (EPO) production has also been described in patients with lymphoproliferative diseases. The severity of anemia, which may be worsened by an impaired cardiopulmonary function, may profoundly compromise the patients' quality of life and, indirectly, the outcome of cancer bearing patients. Several Authors have reported the clinical activity of recombinant human (rHu)EPO in anemic patients with lymphoproliferative diseases, including CLL. Low serum EPO levels at baseline and EPO levels inappropriately low for the degree of anemia help to identify patients who are likely to respond to EPO. A clear dose-dependent response to EPO has been reported by different Authors and it has been suggested that 5,000 IU should be considered as an appropriate initial dose for the majority of patients. rHuEPO represents a potentially effective and safe therapy for the management of anemia associated with lymphoproliferative diseases. The reduction of red blood cell transfusion requirement, the improvement of quality of life through the remission of fatigue-related anemia are two important results that should be considered in the management of patients with CLL. In prospect, the availability of new rHuEPO molecules with a more prolonged half-life may open new therapeutic avenues.
Graft rejections as well as tolerance are true representation of the specificity, sophistication and redundancy of an elegantly and meticulously designed immune system. Tolerance is in a way similar to the process of self-recognition where lymphoid clones, during development, baring self-reactive receptor are eliminated or rendered in active by "clonal deletion" leading to a state of accommodation and acceptance (anergic). On the other hand, both acute and chronic rejections are manifestation of the purpose of existence of the immune system, which is to defend the host against foreign invaders. Thus, in order to treat (control) graft rejection it is necessary to determine and understand the steps leading to recognition, stimulation, activation, and amplification of the immune system. The first step leading to the initiation of the immune system cascade is recognition. Which can either be direct where donor antigens of the major histocompatibility complex (MHC) expressed on the donor cells (passenger leukocytes) or tissues are recognised by the host immune system. The direct recognition pathway initiates acute graft rejection. Alternatively processed donor MHC peptides presented by the recipient antigen presenting cells (APC) initiate the indirect pathway of immune response, which is as important as the direct recognition especially in chronic rejection. Recognition is followed by the ligation of a series of adhesion molecules starting with an antigen to its specific T-cell receptor (TCR)/cluster of differentiation (CD) complex, expressed on the surface of the T cell. In order for the activation to precede additional costimulatory signals, such as ligation of the CD28/B7, CD4/HLA class II and CD/HLA class I antigens are required. The activation process is accompanied by an increase of cytokines production such as interleukin (IL)-2, IL-12, interferon (INF) and tumour necrosis factor (TNF) by the primed T cell. The complexity and the polymorphic nature of the immune system have necessitated designing agents that inhibit the immune system at different levels. Cyclosporine and Tacrolimus, collectively known as calcineurin inhibitors, seems to act on the IL-2 by inhibiting its production thus leading to a decrease in the proliferation of the activated lymphocyte. Rapamycin, which is similar to Tacrolimus, inhibits graft rejection by blocking IL-2 activation and phosphorylation of 70 S6 kinase thus inhibiting the progression of T-cell from G to S phase. While Cellcept (MMF) reduce the proliferation of T cell by inhibiting purine synthesis and by its action on ionosine monophosphate dehydrogenase. Anti-lymphocyte antibodies (ATG) deplete circulating lymphocytes while selective monoclonal antibodies are directed against IL-2 receptor thus reducing the rate of proliferation of activated T cells. Recently, antibodies to the CD40/CD40 ligand have been shown to induce long-term graft survival with the inhibition of the Th1 cytokines (INF), IL-2 and IL-12 and upregulating the Th2 cytokines IL-4 and IL-10. Lastly graft rejection can be reduced by blockade of the B7/CD28 costimulation pathway with the fusion protein CTLA-4Ig. With the availability of such potent and diverse agents it is now possible to develop multi drug regiments that can depress the immune system at the different steps of the activation cascade, with minimal side effects, thus improving graft and patient survival rates.
Recently, new calcineurin inhibitors, such as tacrolimus (FK-506) and microemulsion cyclosporin, have been approved for maintenance immunosuppression in renal transplant recipients and short-term outcomes have been accumulating. In the majority of patients, these calcineurin inhibitors have been used in combination with new immunosuppressive drugs, such as mycophenolate mofetil (MMF) or sirolimus.
Under these circumstances, a comparison of cyclosporin and tacrolimus provides the answer to a very important controversial issue. Which drug should we choose in individual patients? In an attempt to answer this question, this review compared the use of tacrolimus and cyclosporin in modern immunosuppressive regimens, which have already been published in well designed clinical studies, and discusses how immunosuppression should be individualised in renal transplant patients.
Overall, short-term patient and graft survival with cyclosporin microemulsion and tacrolimus is almost identical. The incidence of acute rejection is generally lower in tacrolimus/azathioprine-than in cyclosporin/azathioprine-treated patients. However, in conjunction with MMF, the difference in the incidence of acute rejection between tacrolimus- and cyclosporin-treated patients became smaller. Adverse events, such as hypertension, hyperlipidaemia and cosmetic changes (gum hypertrophy, hirsutism) seem to be less frequent in tacrolimus-treated than in cyclosporin-treated patients. Recent randomised studies showed that the incidence of post-transplant diabetes mellitus was almost identical between low-dose tacrolimus- and cyclosporin-treated patients.
According to the data discussed in this review, the recommendation on the choice of calcineurin inhibitors at this moment is that either cyclosporin or tacrolimus can be used safely and effectively for patients without any risk factors. However, at our centre, we prefer tacrolimus to cyclosporin in patients with a high risk for rejection, such as those with ABO-incompatibility, delayed graft function, sensitisation, and African American race and some other risk factors, such as hypertension and hyperlipidaemia. Moreover, tacrolimus may be preferable to cyclosporin for women because of hirsutism and for children because of the steroid-sparing effect. We consider that cyclosporin should be chosen when patients experience tacrolimus-related adverse events, such as severe chest pain, tremor, gastrointestinal symptoms and encephalopathy.
In conclusion, well tolerated and effective immunosuppression is feasible with both cyclosporin and tacrolimus. In the current immunosuppressive regimens, a calcineurin inhibitor, either tacrolimus or cyclosporin, is the essential basic standard immunosuppressant. Clinicians need to decide the best means of optimising therapy for individual patients, based on various risk factors, such as risk of rejection, i.e. sensitisation, delayed graft function and ABO-incompatibility, and some adverse events, such as hypertension, hyperlipidaemia and cosmetic changes.
The introduction of recombinant human erythropoietin (RHuEPO) has revolutionised the treatment of patients with anaemia of chronic renal disease. Clinical studies have demonstrated that RHuEPO is also useful in various non-uraemic conditions including haematological and oncological disorders, prematurity, HIV infection, and perioperative therapies. Besides highlighting both the historical and functional aspects of RHuEPO, this review discusses the applications of RHuEPO in clinical practice and the potential problems of RHuEPO treatment.
Hematopoietic growth factors are commonly used in allogeneic and autologous stem cell transplantation. The growth factors most frequently used are human recombinant erythropoietin, filgrastim, and sargramostim, and a number of trials have been done using them either singly or in various combinations for mobilization, post-transplant, and for delayed engraftment. Filgrastim and sargramostim can shorten the neutropenic period and decrease infectious complications post-transplant, thus lowering the cost of both autologous and allogeneic transplants. Erythropoietin has not been particularly effective for mobilization, and studies have not shown its efficacy in reducing red blood cell transfusions in autologous transplants. However, they have been clinically beneficial in allogeneic transplantation and in delayed erythropoiesis post-transplantation. Stem cell factor remains investigational at this time but seems promising. The new long-acting erythropoietin and filgrastim are also introduced here and briefly discussed.
The immunosuppressive drugs cyclosporin A and FK-506, also called calcineurin inhibitors, have been useful for treating immune system-mediated diseases and have truly revolutionized allograft transplantation. Both drugs block T-cell proliferation by mechanisms that involve the inhibition of the key signaling phosphatase calcineurin, hence, the name calcineurin inhibitors. The inhibition of calcineurin activation by cyclosporin A and FK-506 blocks T-cell receptor-mediated production of interleukin-2 (IL-2), a growth factor critical for T-cell proliferation. Recent studies, however, suggest that the effects of the drugs are not limited to blocking calcineurin activation and IL-2 production. This review discusses the molecular actions of cyclosporin A and FK-506.
Anti-neoplastic cytostatic antiproliferative agents, such as methotrexate, 6-mercaptopurine and cyclophosphamide, were originally used as immunosuppressive drugs. Although these agents induced only modest anti-rejection activity, they caused serious non-specific bone marrow suppression, impairing host resistance and increasing the incidence of infections. Unlike these non-selective agents, cyclosporine A, tacrolimus and sirolimus act more selectively on different stages of the T-lymphocyte (T-cell) and B-lymphocyte (B-cell) activation cycles; however, cyclosporine and tacrolimus are nephrotoxic, whereas sirolimus causes hypertriglyceridaemia. Thus, despite this progress, continued efforts must be made to develop and test new, potentially very selective agents. The agent 15-deoxyspergualin moderately inhibits both mitogen-stimulated T-cell proliferation and the generation of cytotoxic T lymphocytes (CTLs) but does not affect the production of interleukin 2 (IL-2). Another drug, FTY720, has a unique action to prevent rejection, by altering the homing of lymphocytes to the lymphoid compartments. The newest members of the family of antiproliferative agents, namely mycophenolate mofetil, leflunomide and brequinar, are potentially more selective than their predecessors. However, the most promising agents are produced using antisense technology. This approach involves the design of antisense oligodeoxynucleotides; these novel drugs are designed to block allograft rejection by blocking selected messenger RNA (mRNA). This review outlines the mechanisms of action, the limitations of application and the molecular or cellular targets of traditional agents, newly developed drugs and also antisense technology, which is an example of a new application of molecular medicine.
A growing list of immunotherapeutic strategies is now being employed to combat lymphoid malignancies. These efforts are warranted given that B-cell lymphomas, particularly those of the common follicular subtype, are among the most "immune-responsive" of all human cancers. Although systemic cytokine therapies for B-cell malignancies have been largely disappointing to date, monoclonal antibody therapies, principally the anti-CD20 antibody rituximab, have already made enormous impact on the treatment algorithm for many B-cell lymphomas. Therapeutic vaccines targeting the tumor-specific immunoglobulin idiotype have demonstrated promising results against lymphomas in phase I/II studies and are currently being evaluated in phase III randomized trials. Additional vaccine therapies being developed include those based on dendritic cells, recombinant idiotype proteins, DNA, heat shock proteins, and gene-modified tumor cells. It is hoped that immunotherapeutic agents, used in tandem or in combination, may someday allow effective treatment of lymphoid malignancies and delay or even replace the need for conventional cytotoxic therapies.
Immunosuppressive Agents Encyclopedic Reference of Molecular Pharmacology
- V Kaever
- M Szamel
Encyclopedic Reference of Molecular Pharmacology
- V Kaever
- M Szamel
- V. Kaever