biostudies-literatureGan PYNational Health and Medical Research Council of Australia1365-1374https://www.ebi.ac.uk/biostudies/studies/S-EPMC6683705biostudies-literatureUnknown30(8)<h4>Background</h4>Myeloperoxidase (MPO)-ANCA-associated GN is a significant cause of renal failure. Manipulating autoimmunity by inducing regulatory T cells is potentially a more specific and safer therapeutic option than conventional immunosuppression.<h4>Methods</h4>To generate MPO-specific regulatory T cells, we used a modified protein-conjugating compound, 1-ethyl-3-(3'dimethylaminopropyl)-carbodiimide (ECDI), to couple the immunodominant MPO peptide (MPO_409-428) or a control ovalbumin peptide (OVA_323-339) to splenocytes and induced apoptosis in the conjugated cells. We then administered MPO- and OVA-conjugated apoptotic splenocytes (MPO-Sps and OVA-Sps, respectively) to mice and compared their effects on development and severity of anti-MPO GN. We induced autoimmunity to MPO by immunizing mice with MPO in adjuvant; to trigger GN, we used low-dose antiglomerular basement membrane globulin, which transiently recruits neutrophils that deposit MPO in glomeruli. We also compared the effects of transferring CD4⁺ T cells from mice treated with MPO-Sp or OVA-Sp to recipient mice with established anti-MPO autoimmunity.<h4>Results</h4>MPO-Sp but not OVA-Sp administration increased MPO-specific, peripherally derived CD4⁺Foxp3^- type 1 regulatory T cells and reduced anti-MPO autoimmunity and GN. However, in mice depleted of regulatory T cells, MPO-Sp administration did not protect from anti-MPO autoimmunity or GN. Mice with established anti-MPO autoimmunity that received CD4⁺ T cells transferred from mice treated with MPO-Sp (but not CD4⁺ T cells transferred from mice treated with OVA-Sp) were protected from anti-MPO autoimmunity and GN, confirming the induction of therapeutic antigen-specific regulatory T cells.<h4>Conclusions</h4>These findings in a mouse model indicate that administering apoptotic splenocytes conjugated with the immunodominant MPO peptide suppresses anti-MPO GN by inducing antigen-specific tolerance.Journal of the American Society of Nephrology : JASNApoptotic Cell-Induced, Antigen-Specific Immunoregulation to Treat Experimental Antimyeloperoxidase GN.PMC66837051147388Holdsworth SRKitching ARGan PYO'Sullivan KMOoi JDGodfrey ASOudin VfalseApoptotic Cell-Induced, Antigen-Specific Immunoregulation to Treat Experimental Antimyeloperoxidase GN.<h4>Background</h4>Myeloperoxidase (MPO)-ANCA-associated GN is a significant cause of renal failure. Manipulating autoimmunity by inducing regulatory T cells is potentially a more specific and safer therapeutic option than conventional immunosuppression.<h4>Methods</h4>To generate MPO-specific regulatory T cells, we used a modified protein-conjugating compound, 1-ethyl-3-(3'dimethylaminopropyl)-carbodiimide (ECDI), to couple the immunodominant MPO peptide (MPO_409-428) or a control ovalbumin peptide (OVA_323-339) to splenocytes and induced apoptosis in the conjugated cells. We then administered MPO- and OVA-conjugated apoptotic splenocytes (MPO-Sps and OVA-Sps, respectively) to mice and compared their effects on development and severity of anti-MPO GN. We induced autoimmunity to MPO by immunizing mice with MPO in adjuvant; to trigger GN, we used low-dose antiglomerular basement membrane globulin, which transiently recruits neutrophils that deposit MPO in glomeruli. We also compared the effects of transferring CD4⁺ T cells from mice treated with MPO-Sp or OVA-Sp to recipient mice with established anti-MPO autoimmunity.<h4>Results</h4>MPO-Sp but not OVA-Sp administration increased MPO-specific, peripherally derived CD4⁺Foxp3^- type 1 regulatory T cells and reduced anti-MPO autoimmunity and GN. However, in mice depleted of regulatory T cells, MPO-Sp administration did not protect from anti-MPO autoimmunity or GN. Mice with established anti-MPO autoimmunity that received CD4⁺ T cells transferred from mice treated with MPO-Sp (but not CD4⁺ T cells transferred from mice treated with OVA-Sp) were protected from anti-MPO autoimmunity and GN, confirming the induction of therapeutic antigen-specific regulatory T cells.<h4>Conclusions</h4>These findings in a mouse model indicate that administering apoptotic splenocytes conjugated with the immunodominant MPO peptide suppresses anti-MPO GN by inducing antigen-specific tolerance.2019-01-01T00:00:00Z2019 Aug2025-04-06T19:30:12.846Z2025-04-06T19:30:12.846ZS-EPMC66837053133769010.1681/asn.201809095510.1681/ASN.2018090955