Therapeutic preparations of IVIg contain naturally occurring anti–HLA-E antibodies that react with HLA-Ia (HLA-A/-B/-Cw) alleles

Abstract

Key Points Therapeutic preparations of IVIg have high levels of HLA (Ia and Ib) reactivity. Anti–HLA-E mAbs mimicked IVIg HLA-I reactivity. Anti–HLA-E mAbs might be useful in suppressing HLA antibody production similar to IVIg and in the way that anti-RhD Abs suppress production.

Immunobiology of Allograft Human Leukocyte Antigens in the New Microenvironment

“…It is in this regard that our earlier report described how-by immunizing a non-classical HLA-Ib antigen, β2m-free recombinant HLA-E-we generated a group of mAbs that reacted not only to HLA-E but also to other HLA-I molecules. The anti-HLA-E mAb TFL-006 reacted with 31 HLA-A alleles, 50 HLA-B alleles and 16 HLA-C alleles in addition to reacting well with HLA-G and HLA-F [84,85]. Such a polyreactive mAb is a result of the immunogenicity of the amino acid sequences in the HLA-E that are common to all other HLA.…”

“…Although generated by immunizing recombinant β2m-free HLA-E, they bound to all HLA-I molecules coated onto microbeads, which were monitored on a Luminex platform. Two of these anti-HLA-E mAbs (TFL-006 and TFL-007) bound to HLA-A, -B, -Cw, -F and -G [84,85], and these polyreactive mAbs recognized peptide sequences shared by all HLA classI molecules [86][87][88].What is most important, both TFL-006 and TFL-007 suppressed secretion of anti-HLA antibodies by activated B cells [92] and also the blastogenesis and proliferation of activated CD4+ T lymphocytes [93]. It was postulated that TFL-006 and TFL-007 were able to bind to the shared epitopes in β2m-free HLA, which were previously hidden in the presence of β2m-associatedHLA.…”

“…The first is similar to the hypersensitivity reaction-like Arthus vasculitisthat occurs in experimental settings following the injection of antigens. This is the interaction that may occur between donor antigens in endothelial linings (such as in vessels and glomeruli) and antibodies that may pre-exist in recipients: such antibodies do occur in the circulation of all people during their life span as pre-existing natural antibodies [84,87,[97][98][99][100][101][102][103], either masked or free [104].The other kind of immune response occurs as a consequence of inflammatory cytokine and/or chemokine being released by allograft-infiltrating immune cells, which may include components of both innate and adaptive immunity. The cytokines may mediate upregulation of β2m-free HLA and HLA-II, which are known to occur on activated lymphocytes, and may mediate shedding of the HLA in the allograft microenviroment and circulation, constituting a pool of soluble (s) HLA.…”

“…Generating monospecific mAbs for every one of the HLA alleles would the first step. Recently, the Terasaki Foundation Laboratory has managed to identify and characterize one such HLA-I-specific monospecific mAb [84,85].…”

Immunoglobulin (Ig)G purified from human sera mirrors intravenous Ig human leucocyte antigen (HLA) reactivity and recognizes one's own HLA types, but may be masked by Fab complementarity-determining region peptide in the native sera

“…IVIg is also used with several autoimmune diseases to suppress effector T and B cells involved in antibody production [4,5]. Paradoxically, all available therapeutic IVIg preparations contain high levels of IgG that react to a wide array of HLA antigens [6] -possibly defeating the very purpose of reducing the levels of anti-HLA antibodies.…”