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

Mepur H Ravindranath,Edward J Filippone,Fatiha El Hilali

doi:10.3390/vaccines9060680

Mepur H Ravindranath, Edward J Filippone + Show 1 more

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https://doi.org/10.3390/vaccines9060680

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Abstract

HLA class-I (HLA-I) polyreactive monoclonal antibodies (mAbs) reacting to all HLA-I alleles were developed by immunizing mice with HLA-E monomeric, α-heavy chain (αHC) open conformers (OCs). Two mAbs (TFL-006 and TFL-007) were bound to the αHC’s coated on a solid matrix. The binding was inhibited by the peptide 117AYDGKDY123, present in all alleles of the six HLA-I isoforms but masked by β2-microglobulin (β2-m) in intact HLA-I trimers (closed conformers, CCs). IVIg preparations administered to lower anti-HLA Abs in pre-and post-transplant patients have also shown HLA-I polyreactivity. We hypothesized that the mAbs that mimic IVIg HLA-I polyreactivity might also possess the immunomodulatory capabilities of IVIg. We tested the relative binding affinities 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 OC, whereas IVIg bound to both CC and OC. The mAbs suppressed blastogenesis and proliferation of PHA-activated T-cells and anti-HLA Ab production by B-cells and expanded T-regs better than IVIg. We conclude that a humanized version of the TFL-mAbs could be an ideal, therapeutic IVIg-mimetic.

Highlights

The monoclonal antibodies (mAbs) bound only to open conformers (OCs), whereas intravenous immunoglobulin (IVIg) bound to both CC and OC
We have shown that mAb TFL-006 binds well on acid-denatured LABScreen beads but not on iBeads, in which β2m-free HCs (OCs) are selectively, enzymatically removed from the regular LABScreen beads [45,46]
The observations point out conclusively that IVIg (a) suppressed blastogenesis and proliferation of T-cells, (b) minimized the HLA class-II (HLA-II) allo-antibody production by B-memory cells of parous women and HLA class-I (HLA-I) antibody production of an immortalized cell line, and (c) expanded T-regs. These effects could be due to the HLA OC-polyreactive Abs present in IVIg

Summary

Introduction

Several studies documented that commercial IVIg inhibited PHA- or cytokine-induced T-cell activation and proliferation, both in vitro and in vivo [59,60,61,62,63,64,65,66,67,68,69,70,71,72,73]. IVIg vs HLA-I Polyreactive mAbs. Previous literature documented that commercial IVIg inhibited PHA- and BackgroundT-cell and Hypothesis cytokine-induced activation and proliferation and significantly reduced the number. IVIg notwith onlyinflammatory inhibited PHAof T-lymphocytes in vivodocumented in a placebo-controlled trial in patients my-and opathies, but it was activation capable of and suppressing antibody in reduced patients under cytokine-induced. IVIg transplantation, is extensively used in patients with transfusion, end-stage organ disease in as patients well as allograft end-stage organ disease

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