Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human severe combined immunodeficiency (SCID) can result from mutations in any one of at least seven different genes, including those for adenosine deaminase, the common cytokine receptor gamma chain, Janus kinase 3, IL-7 receptor alpha chain, recombinase activation genes 1 and 2, and CD45. Except for adenosine deaminase, knowledge concerning the latter causes of human SCID has accrued since 1993. Advances in the treatment of this syndrome have been no less significant. Since 1982 it has been possible, by rigorous depletion of T cells from the donor marrow, to use related marrow donors other than HLA-identical siblings for successful treatment of infants with this condition. The success rate with the latter type of transplant exceeds 95% if a transplant can be performed within the first 3.5 mo of life, making early diagnosis crucial. Recently, gene therapy has also been successful in infants with X-linked SCID.
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PMID:Advances in the understanding and treatment of human severe combined immunodeficiency. 1133 59

The BCR-ABL gene that arises in chronic myeloid leukaemia (CML) is a neoantigen. Peptides derived from the BCR-ABL fusion junction may therefore be immunogenic, if appropriately presented to the immune system. This article reviews data demonstrating that certain junctional peptides will bind to HLA molecules, and that these peptides will elicit specific T-lymphocyte responses in vitro, in both normal subjects and in CML patients. The clinical relevance of these observations is discussed.
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PMID:BCR-ABL fusion peptides and cytotoxic T cells in chronic myeloid leukaemia. 1169 42

The BCR-ABL oncogene is central in the pathogenesis of chronic myeloid leukemia (CML). Here, tandem nanospray mass spectrometry was used to demonstrate cell surface HLA-associated expression of the BCR-ABL peptide KQSSKALQR on class I-negative CML cells transfected with HLA-A*0301, and on primary CML cells from HLA-A3-positive patients. These patients mounted a cytotoxic T-lymphocyte response to KQSSKALQR that also killed autologous CML cells, and tetramer staining demonstrated the presence of circulating KQSSKALQR-specific T cells. The findings are the first demonstration that CML cells express HLA-associated leukemia-specific immunogenic peptides and provide a sound basis for immunization studies against BCR-ABL.
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PMID:Direct evidence that leukemic cells present HLA-associated immunogenic peptides derived from the BCR-ABL b3a2 fusion protein. 1169 67

Since STI571, a BCR-ABL tyrosine kinase inhibitor, has made a great therapeutic advance in the management of CML, we have to reconsider the treatment protocol for chronic phase CML. Interferon-alpha (IFN-alpha) will be replaced with STI571 therapy. However, some patients are reported to become refractory to STI571, and it is unclear whether STI571 therapy alone may be sufficient to induce long-term survival in CML. There are also important progress in the field of allogeneic hematopoietic stem cell transplantation (SCT); i.e. minitransplant(non-myeloablative SCT) and cord blood stem cell transplantation. Currently, newly-diagnosed CML patients in chronic phase should be initially treated with STI571. If the patients are appropriate candidates for allogeneic SCT and have HLA-indentical sibling donors, allogeneic SCT should be conducted within one year. The other patients should also receive related or unrelated allogeneic SCT if Ph suppression is insufficient with STI571 therapy for several months. The patients who are not candidates for allogeneic SCT may be treated with IFN-alpha and/or Hydrea(or cytosine arabinoside) in addition to STI571 if they become refractory to STI571. Since each therapeutic modality has different risk and benefits, informed consent is very important to determine the treatment plan for individual patients.
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PMID:[Treatment plan and informed consent]. 1176 45

Lack of standardization of methods and detection limits contributes to the controversial results regarding microchimerism after organ transplantation and has prompted the development of a standardized, reproducible, "easy-to-use" flow cytometric method for this type of "rare event analysis".EDTA-blood of healthy, HLA-typed donors was stained simultaneously with FITC- and biotin-labeled HLA-class I antibodies (One Lambda) as well as Cy5-PE-labeled CD45 (Medac, Hamburg) according to a standard protocol and analysed on a Coulter EPICS XL Flow cytometer (FCM). An absolute range of positivity (mean MESF+/- 1 STD) was determined for 22 HLA-specific antibodies. The range of positivity ranged between 5000 and 20,000 MESF (anti-A23, 24(9) FITC) and 40,000-140,000 (anti-Bw6 FITC). The frequency of nonspecific positive signals using nonstained cells, isotype-controls and irrelevant HLA antibodies was between 0.01% and about 0.5%, in some samples up to 1.4%, with an MESF between 8000 and 150,000, thus interfering clearly with the defined positive range of most antibodies tested. Using an "HLA antibody cocktail", combining FITC- and PE-labeled antibodies for different HLA specificities and thereby creating an internal control, the identification of donor cells was improved but was only rarely applicable. Due to the lack of highly reactive antibodies, FCM analysis was not suitable for the reliable identification of very low numbers of donor hematopoetic cells despite the theoretical advantages of flow cytometric detection of rare events. The single parameter approach was hampered by a significant frequency of nonspecific positive signals, which were easily mistaken as specific (true) positive signals, whereas the multiparameter approach could only be used in selected cases.
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PMID:Flow cytometric "rare event analysis": a standardized approach to the analysis of donor cell chimerism. 1198 19

The development of chronic rejection is the major limitation to long-term allograft survival. HLA class I Ags have been implicated to play a role in this process because ligation of class I molecules by anti-HLA Abs stimulates smooth muscle cell and endothelial cell proliferation. In this study, we show that ligation of HLA class I molecules on the surface of human aortic endothelial cells stimulates phosphorylation of Src, focal adhesion kinase, and paxillin. Signaling through class I stimulated Src phosphorylation and mediated fibroblast growth factor receptor (FGFR) translocation to the nucleus. In contrast, Src kinase activity was not involved in class I-mediated transfer of FGFR from cytoplasmic stores to the cell surface. Inhibition of Src protein kinase activity blocked HLA class I-stimulated tyrosine phosphorylation of paxillin and focal adhesion kinase. Furthermore, HLA class I-mediated phosphorylation of the focal adhesion proteins and FGFR expression was inhibited by cytochalasin D and latrunculin A, suggesting a role for the actin cytoskeleton in the signaling process. These findings indicate that anti-HLA Abs have the capacity to transduce activation signals in endothelial cells that may promote the development of chronic rejection.
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PMID:Ligation of HLA class I molecules on endothelial cells induces phosphorylation of Src, paxillin, and focal adhesion kinase in an actin-dependent manner. 1202 34

Copolymer 1 (Cop 1, Copaxone [Teva Marion Partners, Kansas City, Missouri, USA]), a random amino acid copolymer of tyrosine (Y), glutamic acid (E), alanine (A), and lysine (K), reduces the frequency of relapses by 30% in relapsing-remitting multiple sclerosis (MS) patients. In the present study, novel random four-amino acid copolymers, whose design was based on the nature of the anchor residues of the immunodominant epitope of myelin basic protein (MBP) 85-99 and of the binding pockets of MS-associated HLA-DR2 (DRB1*1501), have been synthesized by solid-phase chemistry. Poly (Y, F, A, K) (YFAK) inhibited binding of the biotinylated MBP 86-100 epitope to HLA-DR2 molecules more efficiently than did either unlabeled MBP 85-99 or any other copolymer including Cop 1. Moreover, YFAK and poly (F, A, K) (FAK) were much more effective than Cop 1 in inhibition of MBP 85-99-specific HLA-DR2-restricted T cell clones. Most importantly, these novel copolymers suppressed experimental autoimmune encephalomyelitis, induced in the susceptible SJL/J (H-2(s)) strain of mice with the encephalitogenic epitope PLP 139-151, more efficiently than did Cop 1. Thus, random synthetic copolymers designed according to the binding motif of the human immunodominant epitope MBP 85-99 and the binding pockets of HLA-DR2 might be more beneficial than Cop 1 in treatment of MS.
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PMID:Novel synthetic amino acid copolymers that inhibit autoantigen-specific T cell responses and suppress experimental autoimmune encephalomyelitis. 1207 Mar 11

Here we show that the Janus kinase 3 (JAK3) inhibitor 4-(3'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (JANEX-3) exhibits potent anti-GVHD activity and consequently improves the post-BMT survival outcome of C57BL/6 (H-2b) recipient mice transplanted with allogeneic bone marrow/splenocyte (BM/S) grafts from MHC disparate BALB/c mice (H-2d). One hundred percent of the vehicle-treated allograft recipients developed severe GVHD and died with a median survival of 41 days. Treatment of recipient mice with JANEX-3 (30 mg/kg/day, 3 x/day) after the onset of rapidly progressive severe GVHD in the 3rd week after BMT significantly improved the survival of BMT recipients with GVHD and prolonged the median survival time to 78 days (P < 0.0001, log-rank test). The probability of survival at two and three months post-BMT was 6 +/- 6% and 0 +/- 0% for vehicle-treated control mice and 100 +/- 0% and 38 +/- 17% for mice treated with JANEX-3. These results prompted the hypothesis that JAK3 plays a pivotal role in the pathophysiology of GVHD. To test this hypothesis, we examined if mice transplanted with allogeneic BM/S grafts from Jak3 knockout mice Jak3-/- develop GVHD. The allografts from (Jak3-/-) C57BL/6 (H-2b) mice rescued MHC-disparate recipient BALB/c mice (H-2d) of the lethal toxicity of TBI without causing fatal GVHD. Taken together, these observations establish JAK3 as a key mediator of severe GVHD after allogeneic BMT in the context of a major-HLA disparity.
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PMID:Treatment of post-bone marrow transplant acute graft-versus-host disease with a rationally designed JAK3 inhibitor. 1238 28

Chronic myeloid leukemia (CML) is a clonal disease of hematopoietic stem cells caused by a reciprocal translocation of the long arms of chromosomes 9 and 22. In human leukocyte antigen A*0201(+) (HLA-A*0201(+)) individuals, response after interferon-alpha (IFN-alpha) was shown to be associated with the emergence of CML-specific cytotoxic T cells that recognize PR-1, a myeloblastin (MBN)-derived nonapeptide. In contrast, imatinib potently induces remissions from CML by specific inhibition of the ABL tyrosine kinase. Here, we explored molecular regulations associated with CML responses under different treatment forms using cDNA-array. Expression of MBN was found to be down-regulated in remission under imatinib therapy (0 of 7 MBN(+) patients). In contrast, MBN transcription was readily detectable in the peripheral blood in 8 of 8 tested IFN-alpha patients in complete remission (P =.0002). IFN-alpha-dependent MBN transcription was confirmed in vitro by stimulation of peripheral blood mononuclear cells (PBMCs) with IFN-alpha and by IFN-alpha-mediated activation of the MBN promoter in reporter gene assays. Finally, with the use of HLA-A*0201-restricted, MBN-specific tetrameric complexes, it was demonstrated that all of 4 IFN-alpha-treated patients (100%), but only 2 of 11 imatinib patients (19%), in complete hematological or cytogenetic remission developed MBN-specific cytotoxic T cells (P =.011). Together, the induction of MBN expression by IFN-alpha, but not imatinib, may contribute to the specific ability of IFN-alpha to induce an MBN-specific T-cell response in CML patients. This also implies that the character of remissions achieved with either drug may not be equivalent and therefore a therapy modality combining IFN-alpha and imatinib may be most effective.
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PMID:Interferon-alpha, but not the ABL-kinase inhibitor imatinib (STI571), induces expression of myeloblastin and a specific T-cell response in chronic myeloid leukemia. 1239 22

Chronic myeloid leukemia (CML) appears an ideal and exciting immunological target. Novel and rational immunotherapy may therefore play an important adjuvant role in the treatment of CML patients. Peptides derived from the BCR-ABL fusion region have been shown to be immunogenic and are able to stimulate the production of BCR-ABL-specific T cell lines and clones. In this study, A 280 bp multiple epitope region of BCR-ABL fusion antigen was designed and synthesized. This region contains three BCR-ABL antigen epitopes which can bind to HLA-A2, HLA-A3 and HLA-DR11 molecules, respectively, and epitopes of cholera toxin B (CTB) and tetanus toxoid (TT) which are able to elicit vigorous T cell responses. The fusion antigen gene has highly been expressed in E. coli and the purified fusion protein reserved satisfied activity and antigenicity. The results of this investigation provided a basis for further research on the developing specific T cell immunotherapy of CML.
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PMID:[Synthesis, Cloning and Expression of a Multiple Epitope Antigen of BCR-ABL Fusion Gene] 1257 95


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