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)

We previously reported that the combined treatment of perioperative administration of donor splenocytes via the recipient's portal vein (DSPV) and a short-course Tacrolimus significantly prolonged the survival of fully allogenic grafts in rat small bowel transplantation (SBTX). In the present study we examined whether this effect depended on the quantity of the administered alloantigens in DSPV. In addition, we examined the expression of the surface antigen on T cells of the splenocytes and the induced toleragenic factor, according to the tolerant recipients which in our previous report had shown the prolongation of allogenic transplant small bowel graft survival by the combined treatment of DSPV (1 x 10(8) donor splenocytes) and a short-course Tacrolimus. Donor splenocytes were prepared from Brown-Norway (BN (RT1n)) rat spleens for Lewis (LEW (RT1l)) recipients. The recipients (n = 10), treated with a short course of Tacrolimus (0.5 mg/kg, 0 to 3 days postoperatively) only showed graft rejection with an average of 6.3 +/- 1.0 days postoperatively. However, the combined treatment, consisting of DSPV of 1 x 10(8) donor splenocytes and a short course Tacrolimus significantly prolonged graft survival to 12.7 +/- 2.1 days (n = 12, P < 0.01). DSPV of less than 1 x 10(8) donor splenocytes (5 x 10(7) cells and 2.5 x 10(7)) could not prolong the graft or animal survival under a short-course Tacrolimus treatment. In the tolerant recipients, the CD4 and CD8 percentages of splenocytes were not significantly different from those of control rats or recipients that were treated with short-course Tacrolimus alone. Nevertheless, the percentage of Tcr-alpha beta+ cells expressing IL-2 receptor (R) was significantly lower than in either control rats or the recipients with short-course Tacrolimus. In the suppression assay to one-way mixed lymphocyte response, a toleragenic factor was suggested to the present in the serum of the tolerant recipients. In the present study, it was suggested that the effects of the combined treatment of DSPV and short-course Tacrolimus for the prolongation of graft survival in the rat allogenic SBTX should depended on the quantity of the antigens administered into the portal vein. The beneficial effects of this treatment were reflected in the suppression of IL-2R on the recipient's splenocytes, and tolerogenic factor(s) might subsequently be induced in the tolerant recipient's serum.
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PMID:Experimental study of combined treatment with tacrolimus and donor splenocytes via the portal vein in small bowel transplantation. 1169 55

Tacrolimus inhibits lymphocyte responses by blocking calcium-dependent signalling pathways important in IL-2 generation. Daclizumab, a humanized monoclonal antibody, binds with high affinity to the Tac subunit of the IL-2 receptor complex. We reasoned therefore that the absence of IL-2R should permit lower doses of tacrolimus and thereby less toxicity. Twenty-eight patients were randomized and followed for 6 months: Group 1, high dose (HD) tacrolimus (trough 12-17 ng/mL; n = 13); Group 2, low dose (LD) tacrolimus (trough 5-10 ng/mL; n = 15). All patients received daclizumab induction (2 mg/kg) on days 0 and 14, mycophenolate mofetil (2 g/d except for one patient who received 1 g) and rapid prednisone taper. Serious infections were minimal in both groups. Hospitalizations, for various reasons, were HD (n = 12) and LD (n = 6). All patients and grafts survived for the 6-month study period. There was one rejection episode in a non-compliant patient at 101 d. LD tacrolimus appears equally effective as HD tacrolimus in preventing rejection episodes and may be associated with fewer adverse events.
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PMID:Daclizumab induction/tacrolimus sparing: a randomized prospective trial in renal transplantation. 1237 41

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