T regulatory Cell-mediated Immunotherapy for Solid Organ Transplantation: A Clinical Perspective

Khan, Mohammad Afzal

doi:10.2119/molmed.2016.00050

Cited by 16 publications

(13 citation statements)

References 182 publications

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“…Treg constitute 3-10% of the naive peripheral CD4 + T cell pool in humans, are especially enriched in the CD4 + CD25 high population, may express the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, i.e., CD152), constitutively express the intracellular transcription factor FoxP3, and express low levels of CD127 low (IL-7 receptor) [3][4][5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Increased frequency of CD4⁺CD25^highCD127^lowT cells early after lung transplant is associated with improved graft survival – a retrospective study

et al. 2020

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In this retrospective study, we analyzed the presence of any association of three CD4 + CD25 high regulatory T-cell subpopulations at 3 weeks after lung transplantation with the later incidence of chronic lung allograft dysfunction and graft survival. Among lung-transplanted patients between January 2009 and April 2018, only patients with sufficient T-cell measurements at 3 weeks after transplantation were included into the study. Putative regulatory T cells were defined as CD4 + CD25 high T cells, detected in peripheral blood and further analyzed for CD127 low , FoxP3 + , and CD152 + using fluorescence-activated cell sorting (FACS) analysis. Associations of regulatory T cells with chronic lung allograft dysfunction (CLAD) and graft survival were evaluated using Cox analysis. During the study period, 724 (71%) patients were included into the study. Freedom from chronic lung allograft dysfunction (CLAD) and graft survival amounted to 66% and 68% at 5 years. At the multivariable analysis, increasing frequencies of CD127 low were associated with better freedom from CLAD (hazard ratio for each 1% increase of %CD127 low , HR = 0.989, 95% CI = 0.981-0.996, P = 0.003) and better graft survival (HR = 0.991, 95% CI = 0.984-0.999, P = 0.026). A higher frequency of CD127 low regulatory T cells in peripheral blood early after lung transplantation estimated a protective effect against chronic lung allograft dysfunction, mortality, and re-transplantation.

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Section: Introductionmentioning

confidence: 99%

Increased frequency of CD4⁺CD25^highCD127^lowT cells early after lung transplant is associated with improved graft survival – a retrospective study

et al. 2020

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“…Tregs play a central role in establishing immunological tolerance and suppress autoimmunity ( 15 , 16 ). A number of preclinical and clinical studies highlighted the therapeutic potential of these cells in organ transplantation, but pathological or beneficial effects of Tregs on rejecting allografts are still not very clear ( 15 , 17 – 23 ).…”

Section: Introductionmentioning

confidence: 99%

“…Previously, we reported that Treg-mediated immunotherapy has potential to preserve the microvasculature of transplanted tracheae and thereby to rescue the allografts from a sustained hypoxic/ischemic phase, which limits airway tissue remodeling ( 23 , 37 ). Our findings demonstrated that Treg reconstitution favored reestablishment of donor–recipient microvasculature as compared to rejecting allografts on all time points studied.…”

Section: Introductionmentioning

confidence: 99%

C5a Blockade Increases Regulatory T Cell Numbers and Protects Against Microvascular Loss and Epithelial Damage in Mouse Airway Allografts

Khan¹,

Alanazi²,

Ahmed³

et al. 2018

Front. Immunol.

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Microvascular injury during acute rejection has been associated with massive infiltration of CD4+ T effector cells, and the formation of complement products (C3a and C5a). Regulatory T cells (Tregs) are potent immunosuppressors of the adaptive immune system and have proven sufficient to rescue microvascular impairments. Targeting C5a has been linked with improved microvascular recovery, but its effects on the Treg and T effector balance is less well known. Here, we demonstrate the impact of C5a blockade on Treg induction and microvascular restoration in rejecting mouse airway allografts. BALB/c→C57BL/6 allografts were treated with a C5a-neutralizing l-aptamer (10 mg/kg, i.p. at d0 and every second day thereafter), and allografts were serially monitored for Treg infiltration, tissue oxygenation (tpO2), microvascular blood flow, and functional microvasculature between donor and recipients during allograft rejection. We demonstrated that C5a blocking significantly leads to enhanced presence of Tregs in the allograft, reinstates donor–recipient functional microvasculature, improves tpO2, microvascular blood flow, and epithelial repair, followed by an upregulation of IL-5, TGF-β, IL-10 vascular endothelial growth factor, and ANGPT1 gene expression, while it maintained a healthy epithelium and prevented subepithelial collagen deposition at d28 posttransplantation. Together, these data indicate that inhibition of C5a signaling has potential to preserve microvasculature and rescue allograft from a sustained hypoxic/ischemic phase, limits airway tissue remodeling through the induction of Treg-mediated immune tolerance. These findings may be useful in designing anti-C5a therapy in combination with existing immunosuppressive regimens to rescue tissue/organ rejection.

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“…Tregs are anergic, require interleukin (IL)-2 for survival and growth, and suppress proliferation and functional activity of CD4+CD25− cells 4 . Several studies have demonstrated that Tregs can prevent autoimmunity, suppress the immune response to tumors, and inhibit transplant graft rejection 1 , 5 .…”

Section: Introductionmentioning

confidence: 99%

c-Jun N-terminal kinase 1 defective CD4+CD25+FoxP3+ cells prolong islet allograft survival in diabetic mice

Tripathi

Cheekatla

Paidipally

et al. 2018

Sci Rep

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CD4+CD25+FoxP3+ cells (Tregs) inhibit inflammatory immune responses to allografts. Here, we found that co-transplantation of allogeneic pancreatic islets with Tregs that are defective in c-Jun N-terminal kinase 1 (JNK1) signaling prolongs islet allograft survival in the liver parenchyma of chemically induced diabetic mice (CDM). Adoptively transferred JNK1−/− but not wild-type (WT) Tregs survive longer in the liver parenchyma of CDM. JNK1−/− Tregs are resistant to apoptosis and express anti-apoptotic molecules. JNK1−/− Tregs express higher levels of lymphocyte activation gene-3 molecule (LAG-3) on their surface and produce higher amounts of the anti-inflammatory cytokine interleukin (IL)-10 compared with WT Tregs. JNK1−/− Tregs inhibit liver alloimmune responses more efficiently than WT Tregs. JNK1−/− but not WT Tregs are able to inhibit IL-17 and IL-21 production through enhanced LAG-3 expression and IL-10 production. Our study identifies a novel role of JNK1 signaling in Tregs that enhances islet allograft survival in the liver parenchyma of CDM.

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T regulatory Cell-mediated Immunotherapy for Solid Organ Transplantation: A Clinical Perspective

Cited by 16 publications

References 182 publications

Increased frequency of CD4⁺CD25^highCD127^lowT cells early after lung transplant is associated with improved graft survival – a retrospective study

Increased frequency of CD4⁺CD25^highCD127^lowT cells early after lung transplant is associated with improved graft survival – a retrospective study

C5a Blockade Increases Regulatory T Cell Numbers and Protects Against Microvascular Loss and Epithelial Damage in Mouse Airway Allografts

c-Jun N-terminal kinase 1 defective CD4+CD25+FoxP3+ cells prolong islet allograft survival in diabetic mice

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T regulatory Cell-mediated Immunotherapy for Solid Organ Transplantation: A Clinical Perspective

Cited by 16 publications

References 182 publications

Increased frequency of CD4+CD25highCD127lowT cells early after lung transplant is associated with improved graft survival – a retrospective study

Increased frequency of CD4+CD25highCD127lowT cells early after lung transplant is associated with improved graft survival – a retrospective study

C5a Blockade Increases Regulatory T Cell Numbers and Protects Against Microvascular Loss and Epithelial Damage in Mouse Airway Allografts

c-Jun N-terminal kinase 1 defective CD4+CD25+FoxP3+ cells prolong islet allograft survival in diabetic mice

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Increased frequency of CD4⁺CD25^highCD127^lowT cells early after lung transplant is associated with improved graft survival – a retrospective study

Increased frequency of CD4⁺CD25^highCD127^lowT cells early after lung transplant is associated with improved graft survival – a retrospective study