Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:The mosaic of immunosuppressive drugs. 1283 79

A total of 1,859 intestinal transplants was reported to UNOS during the past 20 years (1,822 deceased, and 37 living donors). Forty-three US transplant centers reported at least one intestinal transplant, among them, Jackson Memorial Hospital, Nebraska Medical Center and University of Pittsburgh Medical Center were the 3 largest centers, each performing more than 300 cases. The University of Illinois Medical Center performed the most (N = 24) living donor intestinal transplants. The one-, five-, and ten-year graft survival rates of all recipients are 71%, 45%, and 32%. The longest surviving adult intestine transplant is 19 years posttransplant and the longest surviving pediatric transplant is 18 yrs. Both were simultaneous intestine and liver transplants from deceased donors. The first living-donor intestine transplant was reported to UNOS in 1995. The patient received an intestine-alone transplant which functioned for 501 days. The longest surviving living donor intestine transplant is still functioning after 11 years. Among transplants that included the intestine, 37% were intestine-alone transplants, 30% included intestine+liver+pancreas, and 24% were intestine+liver. One-, 5-, and 10-year graft survival rates of intestine-alone recipients were 80%, 44% and 26%; while those for Intestine+liver and intestine+liver+pancreas, were, 62%, 45%, 36%, and 69%, 48%, 33%, respectively. HLA mismatches seemed to have no effect on graft survival for primary intestinal graft recipients, but the most poorly matched (5-6-HLA antigen mismatches) regraft recipients had notably lower graft survival rates. Patients who received ABO blood type compatible intestinal grafts from an "O" donor had a significantly lower graft survival than AB recipients of an A or B donor or those who received ABO identical transplants. Only 4 ABO incompatible intestinal transplants have been reported and all of them have failed. The first ABO incompatible transplant in the US was performed in 1990 and the graft survived for 7 days. The longest survival of an ABO incompatible transplant was 3.5 years. Ischemic time of intestine, patient's and recipient's CMV status had no effect on graft survival. Patients with a history of rejection episodes posttransplant or who had been previously transplanted had significantly lower graft survival rates. Acute rejection, chronic rejection and infection were among the major causes of graft failure. Infection, multiple organ system failure and graft rejection were the major causes of patient death. Induction therapy was used for 67% of all intestine recipients, which is lower than for kidney (83%) but higher than for liver recipients (59%). Thymoglobulin remained the most commonly used antibody since its introduction into intestine transplantation in 1999. In recent years, more patients received Zenapax/Simulect (anti-IL-2 receptor), Campath (anti-CD52) and Rituximab (anti-CD20). These antibodies were usually used in combination with other immunosuppressants. Patients receiving steroids and Campath induction therapy had higher graft and patient survival than other protocols. Prograft, steroids, Cellcept and Rapamycin were the 4 major immunosuppressants used in maintenance therapy. Prograft and steroids have been used more than 20 years since the initiation of the UNOS intestine database in 1990. Among all maintenance immunosuppression protocols, Prograft+steroids (43%), Prograft-alone (14%), Prograft+steroids+ Cellcept (11%), and Prograft+steroids+Rapamycin (6%) are the top 4 major protocols. Patients on Prograft+steroids+Rapamycin had the highest graft and patient survival rates, while those on steroids alone had the lowest.
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PMID:Intestine and multivisceral transplantation in the United States: a report of 20-year national registry data (1990-2009). 2052 78