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J Am Soc Nephrol. 2019 Aug;30(8):1365-1374. doi: 10.1681/ASN.2018090955. Epub 2019 Jul 23.

Apoptotic Cell-Induced, Antigen-Specific Immunoregulation to Treat Experimental Antimyeloperoxidase GN.

Author information

1
Department of Medicine, Centre for Inflammatory Diseases, Monash University, Clayton, Victoria, Australia; and Departments of Poh-yi.gan@monash.edu.
2
Immunology.
3
Department of Medicine, Centre for Inflammatory Diseases, Monash University, Clayton, Victoria, Australia; and Departments of.
4
Nephrology, and.
5
Pediatric Nephrology, Monash Health, Clayton, Victoria, Australia.

Abstract

BACKGROUND:

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.

METHODS:

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 (MPO409-428) or a control ovalbumin peptide (OVA323-339) 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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

ANCA; end stage kidney disease; focal segmental glomerulosclerosis; glomerulonephritis; immunosuppression; tolerance

PMID:
31337690
PMCID:
PMC6683705
[Available on 2020-08-01]
DOI:
10.1681/ASN.2018090955

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