Ignite Creation Date:
2024-05-05 @ 11:55 AM
Last Modification Date:
2024-10-26 @ 9:16 AM
Study NCT ID:
NCT00172666
Status:
UNKNOWN
Last Update Posted:
2006-03-30
First Post:
2005-09-12
Brief Title:
Decoy Receptor 3 DcR3 Polymorphisms in Rheumatoid Arthritis RA and Systemic Lupus Erythematosus SLE
Sponsor:
National Taiwan University Hospital
Organization:
National Taiwan University Hospital
Study Overview
Official Title:
Investigating Genetic Polymorphism of Decoy Receptor 3 DcR3 Gene in Rheumatoid Arthritis and Systemic Lupus Erythematosus
Status:
UNKNOWN
Status Verified Date:
2004-12
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Although SLE and RA are correlated with genetic predisposing factors such as human leukocyte antigen HLA class II both diseases and other genetic factors might have contributed to the development of dysregulated lymphocyte activation and autoimmunity
Decoy receptor 3 DcR3TR6 is a secreted protein belonging to the tumor necrosis factor TNF receptor family It binds to Fas ligand FasL LIGHT and TL1A that are all TNF family members It was noted that soluble or solid phase DcR3-Fc co-stimulated proliferation lymphokine production and cytotoxicity of mouse and human T cells upon T-cell receptor TCR ligation Recently the investigators found that the serum level of soluble DcR3 was higher in SLE patients than in healthy control subjects unpublished data Taken together the investigators propose that in autoimmune diseases such as RA and SLE activated T cells secrete more DcR3 than non-autoimmune controls which may in turn costimulate T cells further and cause dysregulated lymphocyte activation With the aim to establish the possible correlation between DcR3 genetic polymorphisms DcR3 expressions and autoimmune phenotypes the investigators offer this proposal They plan to investigate the single nucleotide polymorphisms SNPs in the DcR3 gene The genetic polymorphisms on the DcR3TR6 gene and circulating DcR3 level will be compared between RA SLE and non-autoimmune control subjects
Decoy receptor 3 DcR3TR6 is a secreted protein belonging to the tumor necrosis factor TNF receptor family It binds to Fas ligand FasL LIGHT and TL1A that are all TNF family members It was noted that soluble or solid phase DcR3-Fc co-stimulated proliferation lymphokine production and cytotoxicity of mouse and human T cells upon T-cell receptor TCR ligation Recently the investigators found that the serum level of soluble DcR3 was higher in SLE patients than in healthy control subjects unpublished data Taken together the investigators propose that in autoimmune diseases such as RA and SLE activated T cells secrete more DcR3 than non-autoimmune controls which may in turn costimulate T cells further and cause dysregulated lymphocyte activation With the aim to establish the possible correlation between DcR3 genetic polymorphisms DcR3 expressions and autoimmune phenotypes the investigators offer this proposal They plan to investigate the single nucleotide polymorphisms SNPs in the DcR3 gene The genetic polymorphisms on the DcR3TR6 gene and circulating DcR3 level will be compared between RA SLE and non-autoimmune control subjects
Detailed Description:
Abnormal immune responses permit sustained production of pathogenic subsets of autoantibodies such as anti-DNA and anti-RNP anti-RBC anti-platelet T cell help is critical to development of full-blown disease CD4 CD8 CD4- CD8- lymphocytes all help autoantibody production in SLE There are multiple abnormalities that permit hyper-activated self-reactive B and T cells to dominate the immune repertoire Defects in cell activation tolerance apoptosis idiotypic networks immune complex clearance and generation of regulatory cells are all accounted for SLE may involve only one organ system at disease onset or may be multi-systemic Rheumatoid inflammation reflexes cause persistent stimulation of T cells by synovial-derived antigens that cross-react with determinants introduced during antecedent exposure to foreign antigens or infectious agents
Decoy receptor 3 DCR3TR6 is a soluble secreted factor that lacks a trans-membrane domain It belongs to the TNFR family and is capable of binding to TNF family members FasL LIGHT and TL1A DcR3TR6 mRNA is expressed at high levels in lymph nodes the spleen and activated T cells DcR3TR6 binds to FasL and inhibits the Fas-FasL interaction and FasL-mediated apoptosis of lymphocytes and several tumor cell lines LIGHT is highly expressed on surface of activated T lymphocytes and macrophages CD8 tumor-infiltrating lymphocyte granulocytes and monocytes but not in the thymus and several human tumor cell lines LIGHT protein triggers apoptosis of several tumor cells expressing both lymphotoxin β receptor LTβR and TR2 It was postulated that DcR3TR6 modulated LIGHT-triggered costimulation via TR2 in T cells Human PBMCs secrete DcR3TR6 after PHA or anti-CD3 The leukocyte aggregation in mixed lymphocyte reaction was inhibited by adding soluble form DcR3 On the other hand it was shown that DcR3TR6 TR2 LIGHT displayed complexity in their interaction The DcR3TR6 expressed in solid phase actually transduced reverse costimulatory signals into the activated T cells Soluble DcR3-Fc or solid-phase DcR3-Fc was found to costimulate proliferation lymphokine production and cytotoxicity of murine and human T cells in the presence of suboptimal TCR ligation Furthermore cross linking Th1 and Th2 cells with solid-phase DcR3-Fc along with suboptimal concentration of anti-CD3 enhanced proliferation of both Th1 and Th2 cells and augmented Th1 but not Th2 cytokine production These strongly suggest that DcR3TR6 delivers costimulation through its ligands on T cells at least part of the costimulation is transduced via LIGHT Recently we found that soluble DcR3TR6 level in circulating plasma in SLE patients was significantly higher than that of non-autoimmune control subjects Plate-bound form DcR3 enhanced proliferation of T cells under suboptimal anti-CD3 stimulation in both normal and SLE patients Addition of soluble DcR3-Fc reduced activation-induced cell death in T cells subjected to anti-CD3 re-stimulation unpublished data Taken together it raises the possibility that genetic polymorphism in DcR3TR6 locus might influence the expression level or function of DcR3 which in turn is implicated in dysregulated lymphocyte activation and autoimmunity With the aim to establish the possible correlation between DcR3 genetic polymorphism DcR3 expression and autoimmune phenotypes we give this proposal We plan to investigate the single nucleotide polymorphisms SNPs in DcR3 gene The genetic polymorphisms on DcR3TR6 gene and circulating DcR3 level will be compared between RA SLE and non-autoimmune control subjects
The specific aims of this project are the following
1 To study the allelic distribution of DcR3 genetic polymorphisms among the population in Taiwan
2 To investigate if there is any DcR3 allele correlate to serum level of DcR3
3 To investigate if the genetic polymorphism on DcR3 gene be associated with autoimmune diseases RA and SLE
Decoy receptor 3 DCR3TR6 is a soluble secreted factor that lacks a trans-membrane domain It belongs to the TNFR family and is capable of binding to TNF family members FasL LIGHT and TL1A DcR3TR6 mRNA is expressed at high levels in lymph nodes the spleen and activated T cells DcR3TR6 binds to FasL and inhibits the Fas-FasL interaction and FasL-mediated apoptosis of lymphocytes and several tumor cell lines LIGHT is highly expressed on surface of activated T lymphocytes and macrophages CD8 tumor-infiltrating lymphocyte granulocytes and monocytes but not in the thymus and several human tumor cell lines LIGHT protein triggers apoptosis of several tumor cells expressing both lymphotoxin β receptor LTβR and TR2 It was postulated that DcR3TR6 modulated LIGHT-triggered costimulation via TR2 in T cells Human PBMCs secrete DcR3TR6 after PHA or anti-CD3 The leukocyte aggregation in mixed lymphocyte reaction was inhibited by adding soluble form DcR3 On the other hand it was shown that DcR3TR6 TR2 LIGHT displayed complexity in their interaction The DcR3TR6 expressed in solid phase actually transduced reverse costimulatory signals into the activated T cells Soluble DcR3-Fc or solid-phase DcR3-Fc was found to costimulate proliferation lymphokine production and cytotoxicity of murine and human T cells in the presence of suboptimal TCR ligation Furthermore cross linking Th1 and Th2 cells with solid-phase DcR3-Fc along with suboptimal concentration of anti-CD3 enhanced proliferation of both Th1 and Th2 cells and augmented Th1 but not Th2 cytokine production These strongly suggest that DcR3TR6 delivers costimulation through its ligands on T cells at least part of the costimulation is transduced via LIGHT Recently we found that soluble DcR3TR6 level in circulating plasma in SLE patients was significantly higher than that of non-autoimmune control subjects Plate-bound form DcR3 enhanced proliferation of T cells under suboptimal anti-CD3 stimulation in both normal and SLE patients Addition of soluble DcR3-Fc reduced activation-induced cell death in T cells subjected to anti-CD3 re-stimulation unpublished data Taken together it raises the possibility that genetic polymorphism in DcR3TR6 locus might influence the expression level or function of DcR3 which in turn is implicated in dysregulated lymphocyte activation and autoimmunity With the aim to establish the possible correlation between DcR3 genetic polymorphism DcR3 expression and autoimmune phenotypes we give this proposal We plan to investigate the single nucleotide polymorphisms SNPs in DcR3 gene The genetic polymorphisms on DcR3TR6 gene and circulating DcR3 level will be compared between RA SLE and non-autoimmune control subjects
The specific aims of this project are the following
1 To study the allelic distribution of DcR3 genetic polymorphisms among the population in Taiwan
2 To investigate if there is any DcR3 allele correlate to serum level of DcR3
3 To investigate if the genetic polymorphism on DcR3 gene be associated with autoimmune diseases RA and SLE
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| NSC 94-2320-B-002-085 | None | None | None |