Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

Therapeutic Potential of HLA-I Polyreactive mAbs Mimicking the HLA-I Polyreactivity and Immunoregulatory Functions of IVIg

Version 1 : Received: 28 April 2021 / Approved: 10 May 2021 / Online: 10 May 2021 (12:30:03 CEST)

A peer-reviewed article of this Preprint also exists.

Ravindranath, M.H.; Hilali, F.E.; Filippone, E.J. Therapeutic Potential of HLA-I Polyreactive mAbs Mimicking the HLA-I Polyreactivity and Immunoregulatory Functions of IVIg. Vaccines 2021, 9, 680. Ravindranath, M.H.; Hilali, F.E.; Filippone, E.J. Therapeutic Potential of HLA-I Polyreactive mAbs Mimicking the HLA-I Polyreactivity and Immunoregulatory Functions of IVIg. Vaccines 2021, 9, 680.

Journal reference: Vaccines 2021, 9, 680
DOI: 10.3390/vaccines9060680

Abstract

HLA class-I (HLA-I) polyreactive monoclonal antibodies (mAbs) reacting to all HLA-I alleles were developed by immunizing HLA-E monomeric heavy chain (HC) (Open Conformers, OCs). Two of the mAbs (TFL-006 and TFL-007) bound to the HC’s coated on a solid matrix. The binding was inhibited by a peptide 117AYDGKDY123, present in all alleles of the six HLA-I isoforms but masked by 2-microglobulin -m) in intact HLA-I trimers (Closed Conformers, CCs). Identical HLA-I polyreactivity is observed in IVIg administered to lower anti-HLA antibodies (Abs) in HLA-sensitized patients, but the mechanism is unknown. We hypothesized that the mAbs that mimic IVIg HLA-I polyreactivity might mimic the immunomodulatory functions of IVIg. We tested the relative binding affinity of the mAbs and IVIg for both OCs- and CCs and compared their effects on (a) the phytohemagglutinin (PHA)-activation T-cells, (b) the production of anti-HLA-II antibody (Ab) by B-memory cells, and anti-HLA-I Ab by immortalized B-cells, and (c) the upregulation of CD4+, CD25+, and Fox P3+ T-regs. The mAbs bound only to OCs, whereas IVIg is bound to both CCs and OCs. The mAbs suppressed blastogenesis and proliferation of PHA-activated T-cells, anti-HLA Ab production by B-cells and expanded the T-regs, better than IVIg. We conclude that a humanized version of the TFL-mAbs could be an ideal therapeutic IVIg-mimetic.

Subject Areas

Intravenous Immunoglobulin (IVIg); Human Leukocyte Antigen-I (HLA-1); Polyreactive mAbs; Monospecific mAbs; Shared epitopes; Immunosuppression; T-cells; B-memory cells; T-regulatory Cells; Blastogenesis, proliferation, Antibody production

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