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

We previously examined the Ig heavy (H) chain gene of pretransplant patients with X-linked SCID (XSCID), having defects in the gene of the IL-2 receptor (R) gamma chain. In the present study, we analyzed two post-transplant XSCID patients, in whom T cell-depleted haploidentical BMT resulted in lymphoid split chimeras, i.e., donor functional T cells coexisting with recipient B cells. Although the recipient B cells produced IgM, no isohemagglutinin or Ag-specific Ab was detected. To investigate the cause of failure to produce Ab in the patients, we sequenced the complementarity determining region 3 (CDR3) and adjacent region of Ig H chain gene, which govern Ab specificity. Among the 64 post-transplant CDR3 junctional sequences, combinatorial and junctional diversity were normal compared with those in age-matched controls. All of the post-transplant joining regions except one clone were equal to germline and the frequency of somatic mutation was significantly lower than that in age-matched controls. The results indicated that T cell reconstitution by BMT does not restore diversification of the Ig gene in the IL-2R gamma chain-deficient B cells, which might be associated with the defect in the Ag-specific Ab production.
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PMID:T cell reconstitution by haploidentical BMT does not restore the diversification of the Ig heavy chain gene in patients with X-linked SCID. 875 Feb 73

The IL-2 receptor (IL-2R) gamma chain is shared among receptors for IL-4, IL-7, IL-9 and IL-15 as well as IL-2. In order to clarify the functional role of these cytokines interacting with the common gamma chain in human early hematopoiesis, we studied expression of the IL-2R gamma chain on purified CD34 positive cells from bone marrow and cord blood. Broad populations of bone marrow mononuclear cells were all found to express the IL-2R gamma chain. CD34 positive cells were purified by CD34 monoclonal antibodies and immunomagnetic beads as representative hematopoietic progenitor cells. It was established that only 38 +/- 10% of CD34 positive bone marrow cells (n = 5) and 35 +/- 12% of CD34 positive cord blood cells (n = 11) expressed the IL-2R gamma chain. CD34(+) IL-2R gamma chain(+) and CD34(+) IL-2R gamma chain(-) cells fractionated by cell sorting were subjected to clonogenic assays that showed granulocyte-macrophage colony-forming cells (CFU-GM) were present evenly in both fractions, whereas erythroid burst-forming cells (BFU-E) were enriched in the CD34(+) IL-2R gamma chain(-) fraction approximately two- to six-fold as compared with CD34(+) IL-2R gamma chain(+) fraction. Such clonogenic features did not differ between the bone marrow and cord blood cases. These results indicate that CD34(+) IL-2R gamma chain(-) cells contain immature cells already committed to the erythroid lineage.
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PMID:IL-2 receptor gamma chain expression on CD34 positive hematopoietic progenitor cells from bone marrow and cord blood. 880 56

The recently cloned cytokine interleukin-15 (IL-15) shares several functional activities with IL-2 in different cell systems. Although IL-15 does not show sequence homology with IL-2, it uses components of the IL-2 receptor (IL-2R) for binding and signal transduction, namely, p75 (beta) and the p64 (gamma) chains of IL-2R. To evaluate whether IL-15 is involved in the activation of granular lymphocytes (GL) in patients with lymphoproliferative disease of granular lymphocytes (LDGL), we evaluated the ability of IL-15 to stimulate GL proliferation, cytotoxic function, and the role of IL-2R beta and gamma molecules on relevant cells. Our results show that IL-15 stimulates cell proliferation and cytotoxic activity of GL in LDGL patients. Reverse-transcriptase polymerase chain reaction (RT-PCR) and phenotypic analyses using the anti-IL-2R gamma-chain-specific TUGh4 monoclonal antibody (MoAb) indicate that both CD3+ and CD3- GL express the p64 IL-2R, a result previously unknown. IL-15 activity was inhibited by antibodies against p75 and p64 IL-2R chains, while no inhibitory effects are detectable with anti-p55 IL-2R antibody. The association of anti-p75 and anti-p64 IL-2R MoAbs resulted in a nearly complete (95%) inhibition of IL-15-induced GL proliferation. Using RT-PCR analysis, we demonstrated that highly purified CD3+ and CD3- GL did not express mRNA for IL-15 or IL-2. By contrast, a clear-cut IL-15 mRNA signal was detected by RT-PCR in patients' peripheral blood mononuclear cells, with monocytes likely accounting for the source of IL-15 in LDGL patients. However, even in concentrated supernatants from enriched monocyte populations, we could not demonstrate the presence of IL-15 protein. Using anti-IL-15 specific MoAbs, a membrane-bound form of this cytokine was demonstrated both on CD3+ and CD3- LDGL cells. By RT-PCR analysis, purified GL from these patients were found to express the message for IL-15 receptor alpha chain. Taken together, these results indicate that both CD3+ and CD3- GL are stimulated by IL-15 and that this cytokine mediates its activity through the beta and gamma chains of the IL-2R, providing further suggestions for the interpretation of the mechanisms that lead to cell expansion in patients with LDGL.
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PMID:Interleukin-15 triggers the proliferation and cytotoxicity of granular lymphocytes in patients with lymphoproliferative disease of granular lymphocytes. 897 93

Genetic engineering has led to the development of fusion protein toxins, which are targeted effector molecules that combine a targeting ligand such as a growth factor with a cytocidal moiety such as a plant or bacterial toxin. The first genetically constructed family of fusion proteins used diphtheria toxin as the toxophore for receptor-binding domain substitution. Diphtheria toxin consists of three domains: an enzymatically active adenosine diphosphate (ADP) ribosyltransferase domain, a hydrophobic transmembrane domain, and a C-terminal receptor-binding domain. Introduction of the enzymatically active domain into the cytosol via receptor-mediated endocytosis results in inhibition of protein synthesis by ADP ribosylation of elongation-factor 2. DAB(486)IL-2, in which the native receptor-binding domain of diphtheria toxin was replaced with the full-length interleukin-2 (IL-2) gene, was capable of intoxicating high-affinity IL-2 receptor-bearing cells in vitro with an IC(50) of 10(-10) M; whereas, cells lacking the full component of the high-affinity IL-2 receptor (p55, p75, p64) were relatively resistant (IC(50) of 10(-8) M). Because of a short in vivo half-life of DAB(486)IL-2, efforts to reengineer the molecule were undertaken, leading to the DAB(389)IL-2 construct, which had a twofold to threefold higher Kd than DAB(486)IL-2 and a longer half-life, resulting in a tenfold increase in potency. Thus far, the clinical activity of both IL-2 chimeric fusion toxins has been similar, with the DAB(389)IL-2 molecule displaying more favorable pharmacokinetics.
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PMID:DAB(389)IL-2 (denileukin diftitox, ONTAK): a new fusion protein technology. 1170 60

The distinct thiol redox status in macrophages, either elevated or reduced intracellular content of glutathione (GSH), was confirmed during aging in IL-2 receptor (IL-2R)gamma and Janus family tyrosine kinase (JAK)3 gene-disrupted mice. Oxidative macrophages (OMp) with reduced GSH dominated initially at a younger age in both mice. OMp-dominated JAK3 or IL-2R gamma chain-deficient mice showed shortened life longevity compared with wild-type littermates. These mice elicited spontaneous onsets of inflammatory bowel disease (IBD)-like symptoms accompanied with the conversion of the redox status of macrophages to reductive phenotypes with elevated intracellular GSH. Conversion of OMp to the reductive phenotype by GSH monoethyl ester or by a beta-(1-3)-glucan accelerated the disease onset, concomitant with the skewing from T(h)2 to T(h)1 responses. On the contrary, N,N'-diacetyl cystine dimethylester, which is capable of inducing OMp, delayed the incidence of IBD-like symptoms and improved the survival rate. This implies that the conversion of OMp/T(h)2 to reductive macrophages/T(h)1 may be critical for the disease progression. The study of these mice may provide insight into the mechanisms underlying Crohn's disease and ulcerative colitis.
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PMID:The conversion of redox status of peritoneal macrophages during pathological progression of spontaneous inflammatory bowel disease in Janus family tyrosine kinase 3(-/-) and IL-2 receptor gamma(-/-) mice. 1203 14

Denileukin diftitox, a genetically engineered fusion protein combining the enzymatically active domains of diphtheria toxin and the full-length sequence for interleukin-2 (IL-2), efficiently targets lymphoma cells expressing the high-affinity IL-2 receptor (IL-2R) consisting of the alpha/p55/CD25, beta/p75/CD122, and gamma/p64/CD132 chains. In vitro studies demonstrated that the retinoid X receptor (RXR) retinoid, bexarotene, at biologically relevant concentrations of 10(-6) M to 10(-8) M, upregulated both the p55 and p75 subunits of the IL-2R and enhanced 5- to 10-fold the susceptibility of T-cell leukemia cells to denileukin diftitox. To determine whether this biomodulatory effect could be recapitulated in vivo, we treated 14 patients with relapsed or refractory cutaneous T-cell lymphoma with escalating doses of bexarotene (75 mg/day-300 mg/day) and denileukin diftitox (18 mcg/kg per day x 3 days every 21 days) in a phase 1 trial. Overall response was 67% (4 complete responses, 4 partial responses). Modulation of IL-2R expression was observed at or above a bexarotene dose of 150 mg/day. Four patients experienced grade 2 or 3 leukopenia, and 2 had grade 4 lymphopenia. Our results demonstrate that the combination of denileukin diftitox and bexarotene is well tolerated and that even low doses (150 mg/day) of bexarotene are capable of in vivo upregulation of CD25 expression on circulating leukemia cells.
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PMID:A phase-1 trial of bexarotene and denileukin diftitox in patients with relapsed or refractory cutaneous T-cell lymphoma. 1581 59


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