Monospecific and Polyreactive Monoclonal Antibodies against Human Leukocyte Antigen-E: Diagnostic and Therapeutic Relevance

Ravindranath, Mepur H.; Hilali, Fatiha El

doi:10.5772/intechopen.95235

Cited by 4 publications

(10 citation statements)

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“…We have reported a detailed analysis of HLA-Ia and -Ib reactivities of a monospecific mAb (TFL-033) [ 104 , 105 , 106 , 107 , 108 , 109 ] and the polyreactive mAbs (TFL-006 and TFL-007) [ 109 , 110 , 111 , 112 , 113 ]. The binding affinity of the monospecific mAb TFL-033 was tested using the HLA-E specific amino acid sequence (SARDATA) as well as the binding affinity of the mAb TFL-006 with the most shared sequence 141 AYDGKDY 147 , by inhibiting the binding of mAbs to the beadsets (LABScreen) used on Luminex Platform.…”

Section: The Pattern Of Diversity Of Hla Monoclonal Abs (Mabs)mentioning

confidence: 99%

“…Given the nature of the shared epitopes, mice were immunized with recombinant HCs of HLA-E and the Abs elicited after immunization were examined for binding to different alleles of different HLA isomers [ 104 , 105 , 106 , 107 , 108 , 109 ]. A profile of the antibody specificities of more than 200 mAbs are illustrated in the Table 6 and are described in detail elsewhere [ 104 , 105 , 106 , 107 , 108 , 109 ]. Distinctly, six mAbs were highly polyreactive to β2m-free HCs (Face-2) of all alleles of HLA isoforms.…”

Section: The Immunoregulatory Potential Of Anti-hla-i Mabs Unravels T...mentioning

confidence: 99%

“…Distinctly, six mAbs were highly polyreactive to β2m-free HCs (Face-2) of all alleles of HLA isoforms. The shared epitopes were identified, and the synthetic amino acid sequences were used to inhibit the binding of the polyreactive mAbs [ 109 , 110 , 111 , 112 , 113 ]. Of these, TFL-006 ranks first and TFL-007 ranks second in their strength of polyreactivity as illustrated [ 68 , 110 , 112 , 113 ].…”

Section: The Immunoregulatory Potential Of Anti-hla-i Mabs Unravels T...mentioning

confidence: 99%

“…The specific sequences located on the α1 and α2 domains of HLA-E are indeed the sequences recognized by the monospecific mAb TFL-033. The amino acids on the α1 and α2 domains of HLA-E—respectively, (R 65 D 69 ) and (S 152 )—are essential for recognition by the inhibitory receptors CD94 and NKG2A present on the cell-surface of CD8+ T-cells and NK cells [ 105 , 106 , 107 , 108 , 109 , 134 , 168 , 169 ]. Therefore, the mAb TFL-033 has the potential to block the ligands of inhibitory receptors on the α1 and α2 helices of HLA-E [ 107 , 108 , 109 ].…”

Section: The Major Players In Hla-i-mediated Cellular and Humoral Imm...mentioning

confidence: 99%

“…The amino acids on the α1 and α2 domains of HLA-E—respectively, (R 65 D 69 ) and (S 152 )—are essential for recognition by the inhibitory receptors CD94 and NKG2A present on the cell-surface of CD8+ T-cells and NK cells [ 105 , 106 , 107 , 108 , 109 , 134 , 168 , 169 ]. Therefore, the mAb TFL-033 has the potential to block the ligands of inhibitory receptors on the α1 and α2 helices of HLA-E [ 107 , 108 , 109 ]. When the mAb TFL-033 was tested in vitro on isolated CD3+/CD8+ T-cells both in the presence and absence of PHA, the mAb triggered proliferation of both non-activated and PHA-activated CD8+ T-cells [ 111 ].…”

Section: The Major Players In Hla-i-mediated Cellular and Humoral Imm...mentioning

confidence: 99%

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Role of HLA-I Structural Variants and the Polyreactive Antibodies They Generate in Immune Homeostasis

et al. 2022

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Cell-surface HLA-I molecules consisting of β2-microglobulin (β2m) associated heavy chains (HCs), referred to as Face-1, primarily present peptides to CD8+ T-cells. HCs consist of three α-domains, with selected amino acid sequences shared by all alleles of all six isoforms. The cell-surface HLA undergoes changes upon activation by pathological conditions with the expression of β2m-free HCs (Face-2) resulting in exposure of β2m-masked sequences shared by almost all alleles and the generation of HLA-polyreactive antibodies (Abs) against them. Face-2 may homodimerize or heterodimerize with the same (Face-3) or different alleles (Face-4) preventing exposure of shared epitopes. Non-allo immunized males naturally carry HLA-polyreactive Abs. The therapeutic intravenous immunoglobulin (IVIg) purified from plasma of thousands of donors contains HLA-polyreactive Abs, admixed with non-HLA Abs. Purified HLA-polyreactive monoclonal Abs (TFL-006/007) generated in mice after immunizing with Face-2 are documented to be immunoregulatory by suppressing or activating different human lymphocytes, much better than IVIg. Our objectives are (a) to elucidate the complexity of the HLA-I structural variants, and their Abs that bind to both shared and uncommon epitopes on different variants, and (b) to examine the roles of those Abs against HLA-variants in maintaining immune homeostasis. These may enable the development of personalized therapeutic strategies for various pathological conditions.

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Section: The Pattern Of Diversity Of Hla Monoclonal Abs (Mabs)mentioning

confidence: 99%

Section: The Immunoregulatory Potential Of Anti-hla-i Mabs Unravels T...mentioning

confidence: 99%

Section: The Immunoregulatory Potential Of Anti-hla-i Mabs Unravels T...mentioning

confidence: 99%

Section: The Major Players In Hla-i-mediated Cellular and Humoral Imm...mentioning

confidence: 99%

Section: The Major Players In Hla-i-mediated Cellular and Humoral Imm...mentioning

confidence: 99%

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Role of HLA-I Structural Variants and the Polyreactive Antibodies They Generate in Immune Homeostasis

et al. 2022

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The Impact of Inflammation on the Immune Responses to Transplantation: Tolerance or Rejection?

Ravindranath

Hilali²,

Filippone

2021

Front. Immunol.

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Transplantation (Tx) remains the optimal therapy for end-stage disease (ESD) of various solid organs. Although alloimmune events remain the leading cause of long-term allograft loss, many patients develop innate and adaptive immune responses leading to graft tolerance. The focus of this review is to provide an overview of selected aspects of the effects of inflammation on this delicate balance following solid organ transplantation. Initially, we discuss the inflammatory mediators detectable in an ESD patient. Then, the specific inflammatory mediators found post-Tx are elucidated. We examine the reciprocal relationship between donor-derived passenger leukocytes (PLs) and those of the recipient, with additional emphasis on extracellular vesicles, specifically exosomes, and we examine their role in determining the balance between tolerance and rejection. The concept of recipient antigen-presenting cell “cross-dressing” by donor exosomes is detailed. Immunological consequences of the changes undergone by cell surface antigens, including HLA molecules in donor and host immune cells activated by proinflammatory cytokines, are examined. Inflammation-mediated donor endothelial cell (EC) activation is discussed along with the effect of donor-recipient EC chimerism. Finally, as an example of a specific inflammatory mediator, a detailed analysis is provided on the dynamic role of Interleukin-6 (IL-6) and its receptor post-Tx, especially given the potential for therapeutic interdiction of this axis with monoclonal antibodies. We aim to provide a holistic as well as a reductionist perspective of the inflammation-impacted immune events that precede and follow Tx. The objective is to differentiate tolerogenic inflammation from that enhancing rejection, for potential therapeutic modifications. (Words 247).

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Antibodies for β2-Microglobulin and the Heavy Chains of HLA-E, HLA-F, and HLA-G Reflect the HLA-Variants on Activated Immune Cells and Phases of Disease Progression in Rheumatoid Arthritis Patients under Treatment

Ravindranath

Amato-Menker

et al. 2023

Antibodies

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Rheumatoid arthritis (RA) is a progressive, inflammatory, autoimmune, symmetrical polyarticular arthritis. It is characterized by synovial infiltration and activation of several types of immune cells, culminating in their apoptosis and antibody generation against “altered” autoantigens. β2-microglobulin (β2m)-associated heavy chains (HCs) of HLA antigens, also known as closed conformers (Face-1), undergo “alteration” during activation of immune cells, resulting in β2m-free structural variants, including monomeric open conformers (Face-2) that are capable of dimerizing as either homodimers (Face-3) or as heterodimers (Face-4). β2m-free HCs uncover the cryptic epitopes that can elicit antibodies (Abs). We report here the levels of IgM and IgG Abs against both β2m and HCs of HLA-E, HLA-F, and HLA-G in 74 RA patients receiving immunosuppressive drugs. Anti-β2m IgM was present in 20 of 74 patients, whereas anti-β2m IgG was found in only 8 patients. Abs against β2m would be expected if Abs were generated against β2m-associated HLA HCs. The majority of patients were devoid of either anti-β2m IgM or IgG but had Abs against HCs of different HLA-Ib molecules. The paucity of anti-β2m Abs in this cohort of patients suggests that Abs were developed against β2m-free HLA HCs, such as Face-2, Face-3, and Face-4. While 63 of 68 patients had IgG Abs against anti-HLA-F HCs, 36 and 50 patients showed IgG Ab reactivity against HLA-E and anti-HLA-G HCs, respectively. Evidently, anti-HLA-F HC Abs are the most predominant anti-HLA-Ib HC IgG Abs in RA patients. The incidence and intensity of Abs against HLA-E, HLA-F, and HLA-G in the normal control group were much higher than those observed in RA patients. Evidently, the lower level of Abs in RA patients points to the impact of the immunosuppressive drugs on these patients. These results underscore the need for further studies to unravel the nature of HLA-F variants on activated immune cells and synoviocytes of RA patients.

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Monospecific and Polyreactive Monoclonal Antibodies against Human Leukocyte Antigen-E: Diagnostic and Therapeutic Relevance

Cited by 4 publications

References 128 publications

Role of HLA-I Structural Variants and the Polyreactive Antibodies They Generate in Immune Homeostasis

Role of HLA-I Structural Variants and the Polyreactive Antibodies They Generate in Immune Homeostasis

The Impact of Inflammation on the Immune Responses to Transplantation: Tolerance or Rejection?

Antibodies for β2-Microglobulin and the Heavy Chains of HLA-E, HLA-F, and HLA-G Reflect the HLA-Variants on Activated Immune Cells and Phases of Disease Progression in Rheumatoid Arthritis Patients under Treatment

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