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)

Haploidentical bone marrow transplantation (BMT) is associated with a high risk of severe graft-versus-host disease (GVHD). While pan-T cell depletion of the graft is the most effective means of preventing severe GVHD, it is associated with delayed recovery of T cell function leading to fatal infections. We used two related Pseudomonas exotoxin-based immunotoxins, anti-Tac(Fv)-PE38 and anti-Tac(Fv)-PE38KDEL, that both target the IL-2 receptor on activated T cells, to specifically deplete alloreactive lymphocytes against haploidentical stimulators. The functional capacity of the remaining lymphocytes was tested in proliferative assays against the original haploidentical stimulator and pooled cells from other mismatched donors (third party). We varied the recombinant toxin concentration and schedule to determine the optimum conditions for selective depletion. In 10 experiments, the mean residual reactivity after depletion was 7.6 +/- 1.4% against the haploidentical stimulator and 64.2 +/- 5% against the third party, expressed as a percentage of the undepleted response to the same stimulators. Depletion was shown to be specific for mixed lymphocyte culture (MLC)-activated lymphocytes. The immunotoxin did not affect CFU-GM growth of normal BM cells. This selective depletion of haploidentical alloreactivity could be used to prevent GVHD while conserving immune recovery following haploidentical BMT.
 ...
PMID:Specific depletion of alloreactivity against haplotype mismatched related individuals by a recombinant immunotoxin: a new approach to graft-versus-host disease prophylaxis in haploidentical bone marrow transplantation. 873

A six-year-old boy with homozygous beta-thalassemia in the favorable class 1 risk group received a bone marrow transplant, from his histocompatible sister. He developed grade IV skin and eye graft-versus-host disease (GVHD) following varicella zoster reactivation. Despite the appropriate prophylactic use of cyclosporin A (CsA), methotrexate (MTX), and prompt treatment with high-dose steroids, GVHD progressed resulting in total body epidermal necrolysis. Anti-IL-2 receptor monoclonal antibodies (anti-IL-2R moAb) in combination with steroids were administered to selectively block the activated T cells. After 27 days of daily administration, followed by 17 doses of alternate-day therapy with anti-IL-2R moAb, the severe skin and eye GVHD resolved. The patient, at two years posttransplant, has full engraftment and immune reconstitution without chronic GVHD (cGVHD). In conclusion, we suggest that in the HLA-genoidentical bone marrow transplantation setting, very severe and steroid-resistant GVHD can be controlled through the use of anti-IL-2 receptor antibodies which specifically block the activated IL-2 receptor expressing T cells.
 ...
PMID:Blockade of acute grade IV skin and eye graft-versus-host disease by anti-interleukin-2 receptor monoclonal antibody in genoidentical bone marrow transplantation setting. 967 28

To determine whether administration of G-CSF induces phenotypic or functional changes in T cells, we examined peripheral blood T cells from normal individuals receiving G-CSF for activation antigen and adhesion molecule expression before and after G-CSF administration. G-CSF (10 microg/kg/day) was administered subcutaneously to 14 normal individuals for 3-5 days and their PBMC were serially analyzed with monoclonal Ab (mAb) directed to HLA-DR, CD45RO, CD45RA, CD25, CD122, CD95, CD11a, CD49d, CD44 and CD62L (L-selectin) coupled with anti-CD3 mAb. Among T cells positive for these antigens, only the proportion of T cells expressing L-selectin significantly decreased from 68% to 37% after 3-day G-CSF administration. When peripheral blood CD3+ T cells obtained before and after G-CSF administration were sorted into two populations depending on the expression of L-selectin and tested for their proliferative response to allogeneic B cells, the reactivity of L-selectin- cells to alloantigen stimulation was consistently lower than that of L-selectin+ cells regardless of the exposure to G-CSF. The decrease in the relative number of L-selectin+ cells induced by G-CSF administration may contribute to the unexpectedly low incidence of severe acute GVHD after allogeneic PBSC transplantation.
 ...
PMID:Administration of G-CSF to normal individuals diminishes L-selectin+ T cells in the peripheral blood that respond better to alloantigen stimulation than L-selectin- T cells. 1019 95

Graft-versus-host disease (GVHD), due to the presence of recipient-reactive T cells, limits the usefulness of bone marrow transplantation (BMT) and is a major contributor to patient mortality. To prevent GVHD, murine and human T cells were activated by antigen or mitogens and treated with a genetically engineered form of Pseudomonas exotoxin A (PE) directed against the IL-2 receptor. Treatment with the chimeric toxin eliminated alloreactive cytotoxic T lymphocytes (CTL) as determined by cytotoxicity and mixed lymphocyte culture assays. Precursor frequencies of alloreactive cytotoxic T cells and proliferative T cells were reduced up to 100-fold as shown by limiting dilution assays. Flow cytometric analyses revealed that treatment with the chimeric toxin completely eliminated CD25+ cells from the cultures. Toxin treatment had no significant effect on hematopoietic stem and progenitor cells as determined in vitro by colony-forming assays and in vivo by long-term hematopoietic recovery after 950 rad irradiation. Toxin treatment decreased GVHD in transplanted mice to less than 10% (as compared to 88% in untreated controls). Thus, it is possible to prevent life-threatening GVHD after BMT by using a CD25 receptor-directed toxin to eliminate host-reactive T cells from bone marrow grafts.
 ...
PMID:Prevention of graft-versus-host disease (GVHD) by elimination of recipient-reactive donor T cells with recombinant toxins that target the interleukin 2 (IL-2) receptor. 1019 98

The innate immune system of severe combined immunodeficient (SCID) mice represents an important barrier to the successful engraftment of human cells. Different genetic and pharmacological strategies improve the graft survival. Non-obese diabetic (NOD)-SCID mice are better hosts for reconstitution with human peripheral blood leucocytes (Hu-PBL) because of their reduced natural killer cell and macrophage activity next to defective T and B cell functions. We investigated effects of TM-beta1, a rat monoclonal antibody recognizing the mouse IL-2 receptor beta-chain, on Hu-PBL survival and function in NOD-SCID and SCID mice. Relative to untreated littermates, TM-beta1 improved Hu-PBL survival in SCID and NOD-SCID mice. Moreover, TM-beta1-pretreated NOD-SCID mice displayed significantly better Hu-PBL survival and tissue distribution than TM-beta1-pretreated SCID mice. Irradiation of NOD-SCID mice further enhanced the effects of TM-beta1. However, these animals died within 3 weeks post-grafting due to graft-versus-host disease. Secondary immune responses were evaluated with Hu-PBL from a donor immune to hepatitis B surface antigen (HBsAg). In TM-beta1-pretreated NOD-SCID mice, human HBsAg-specific memory B cells produced high titres of anti-HBsAg immunoglobulin irrespective of the administration of a secondary antigen booster dose. This contrasts with secondary immune responses in TM-beta1-pretreated SCID mice where high titred antigen-specific immunoglobulins were produced when the appropriate antigen booster was given. In conclusion, reducing the function of the innate immune system in immunodeficient mice improves survival of the human graft and can result in an activation of the memory B cells without the need for recall antigen exposure.
 ...
PMID:Mouse strain and conditioning regimen determine survival and function of human leucocytes in immunodeficient mice. 1060 88

When interleukin-2 (IL-2) binds to the IL-2 receptor (IL2-R) on activated T cells, a soluble portion of the receptor (sIL2-R) is released. After allogeneic bone marrow transplantation (BMT), the serum concentration of sIL2-R may, therefore, be a useful surrogate marker for T cell activation that results in acute graft-versus-host disease (aGVHD). To determine if the sIL2-R concentration is a useful marker to help establish a diagnosis of aGVHD, serial sIL2-R concentrations were measured weekly for 4 weeks in 43 patients after allogeneic BMT. Grafts were from HLA-matched siblings (n = 33), 5/6 HLA-matched siblings (n = 3) or matched unrelated donors (n = 7). GVHD prophylaxis included cyclosporine A (CSA)/methotrexate (MTX) (n = 25), solumedrol/CSA (n = 15), or T cell depletion (n = 3). Twenty-three patients developed aGVHD (Grade I, 7; Grade II, 12; Grade III, 4) a median of 28 days after transplant. There was a significant association between a clinical diagnosis of aGVHD and an increase in the sIL2-R concentration (p < 0.001). The mean percent increase (+/-SE) over baseline for patients with a clinical diagnosis of aGVHD was 294% (+/-57%) by week 2 (n = 12), 431% (+/-116%) by week 3 (n = 14), and 650% (+/-315%) by week 4 (n = 9) after BMT. For each 100% increase over baseline, the likelihood of having aGVHD increased by 18%. Six of 20 patients without aGVHD became critically ill and exhibited marked increases in sIL2-R concentrations, similar to patients with a clinical diagnosis of aGVHD who never became critically ill. Fourteen patients without aGVHD who did not become critically ill exhibited negligible increases of sIL2-R in 2- to 4-week period after BMT. These data suggest that serial measurements sIL2-R concentration are helpful in establishing the diagnosis of aGVHD, but are not useful in the most acutely ill patients.
 ...
PMID:Soluble interleukin-2 receptor concentration as a biochemical indicator for acute graft-versus-host disease after allogeneic bone marrow transplantation. 1089 61

GVHD continues to be a major complication after allogeneic hematopoietic stem cell transplantation even when the recipient is given immunosuppression for the prophylaxis of this severe disease. There have been many advances in the prevention and treatment of GVHD, using compounds such as cyclosporine, FK506, mycophenolate mofetil or monoclonal IL-2 receptor antagonist. New strategies seem to include sequential therapy involving the blocking of both endogenous cytokines and alloreactive donor cells. However, further clinical and laboratory studies are needed in order to improve the therapy of established GVHD.
 ...
PMID:New strategies in the treatment of graft-versus-host disease. 1093 79

The plasma levels of a panel of cytokines and cytokine-associated molecules (IL-1alpha, IL-2, IL-4, IL-6, IL-10, IL-12, IL-15, macrophage colony-stimulating factor (M-CSF), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), soluble IL-2 receptor (sIL-2R), soluble tumor necrosis factor receptor I or II (sTNFRI or II)) were assessed in 56 plasma samples of 13 pediatric patients undergoing hematopoietic stem cell transplantation (HSCT, bone marrow in 12 and cord blood in one) from unrelated donors. Eight patients developed severe (grade III-IV) acute GVHD (aGVHD). The plasma IL-6, IL-10, M-CSF, sTNFRI and II levels were significantly high in the severe aGVHD group compared to the mild aGVHD group (grade 0-II). The plasma IL-15 level increased transiently in the early period following HSCT and remained high in the severe aGVHD group even after 4 weeks following HSCT. Based on analysis of the correlations between the kinetics of the plasma cytokine levels after HSCT and the clinical manifestations of aGVHD, IL-15 and/or M-CSF were involved in the development of aGVHD, following elevation of the plasma IL-10 and sTNFRI or II levels. These kinetics suggest that IL-10 and sTNFRs worked as suppressor cytokines and seemed to suppress clinical manifestations of aGVHD. Furthermore, it seemed that the plasma ratio of IL-10/sTNFRII from 5 to 12 weeks following HSCT was linked to the poor outcome in the patients with severe aGVHD, suggesting that IL-10 plays an important role in protecting hosts from transplantation-related complications, including GVHD.
 ...
PMID:Kinetics of plasma cytokines after hematopoietic stem cell transplantation from unrelated donors: the ratio of plasma IL-10/sTNFR level as a potential prognostic marker in severe acute graft-versus-host disease. 1155 Oct 26

The interleukin (IL)-2 receptor has proved an attractive target for T cell-directed therapies. Agents including monoclonal antibodies, single-chain antibody immunoconjugates, radioimmunoconjugates, and, most recently, ligand fusion toxins have demonstrated activity in vitro and in clinical trials in both hematologic malignancies and diseases characterized by proliferation of activated T cells, such as graft-versus-host disease. DAB389IL-2 (ONTAK) is a ligand fusion toxin consisting of the full-length sequence of the IL-2 gene genetically fused to the enzymatically active and translocating domains of diphtheria toxin. DAB389IL-2 and its predecessor, DAB486IL-2, have demonstrated activity in a variety of diseases, including cutaneous T cell lymphoma (CTCL), psoriasis, rheumatoid arthritis, and HIV infection. Further clinical development of IL-2 fusion toxins in CTCL and other hematopoietic malignancies is predicated on identification of the high-affinity IL-2 receptor complex on the malignant cells and on a better understanding of the biological determinants of cytotoxicity of these molecules in vivo.
 ...
PMID:Interleukin-2 fusion toxin: targeted therapy for cutaneous T cell lymphoma. 1159 70

Acute and chronic graft versus host disease (GVHD) remain the major barriers to successful hematopoietic cell transplantation. The induction of GVHD may be divided into three phases: recipient conditioning;donor T-cell activation; andeffector cells mediating GVHD. This review examines GVHD prevention and treatment using this conceptual model as framework. The various pharmacological agents discussed impact on different phases of the GVHD cascade. For example, keratinocyte growth factor and interleukin (IL)-11 are cytokines that may be useful in disrupting phase I of the GVHD cascade by blocking gastrointestinal tract damage, and lowering serum levels of lipopolysaccharide and tumour necrosis factor (TNF)-alpha. Cyclosporin, tacrolimus (FK-506) and sirolimus (rapamycin) are some of the main agents that disrupt phase II (donor T-cell activation). Mycophenolate mofetil and tresperimus probably act on this phase as well. Other novel drugs that affect phase II are tolerance-induction agents such as CTLA-4 and anti-CD40-ligand monoclonal antibodies, and preliminary results using CTLA-4 monoclonal antibody in GVHD prevention are encouraging. Examples of agents that disrupt phase III are the IL-2 receptor antagonist daclizumab and the anti-TNFalpha monoclonal antibody infliximab. These anti-cytokine antibodies have shown promising results in early studies. The most effective approach to GVHD prevention will probably be a combination regimen where the three phases of the GVHD cascade are disrupted. Once GVHD has occurred, all three phases of the cascade are activated. Developments of combination therapy for treatment of both acute and chronic GVHD are likely to yield better results than monotherapy. The numerous new treatment modalities presented should improve the outlook for patients with acute and chronic GVHD.
 ...
PMID:Novel pharmacotherapeutic approaches to prevention and treatment of GVHD. 1192 36


<< Previous 1 2 3 4 5 6 7 Next >>