scholarly journals Induction of Tolerance to Therapeutic Proteins With Antigen-Processing Independent T Cell Epitopes: Controlling Immune Responses to Biologics

2021 ◽  
Vol 12 ◽  
Author(s):  
Evelien Schurgers ◽  
David C. Wraith
Keyword(s):  
T Cell ◽  
Antigen Processing ◽  
Tolerance Induction ◽  
Gene Replacement ◽  
Immunological Tolerance ◽  
Clotting Factor ◽  
T Cell Epitopes ◽  
Enzyme Replacement ◽  
Therapeutic Benefits ◽  
Recombinant Fviii

The immune response to exogenous proteins can overcome the therapeutic benefits of immunotherapies and hamper the treatment of protein replacement therapies. One clear example of this is haemophilia A resulting from deleterious mutations in the FVIII gene. Replacement with serum derived or recombinant FVIII protein can cause anti-drug antibodies in 20-50% of individuals treated. The resulting inhibitor antibodies override the benefit of treatment and, at best, make life unpredictable for those treated. The only way to overcome the inhibitor issue is to reinstate immunological tolerance to the administered protein. Here we compare the various approaches that have been tested and focus on the use of antigen-processing independent T cell epitopes (apitopes) for tolerance induction. Apitopes are readily designed from any protein whether this is derived from a clotting factor, enzyme replacement therapy, gene therapy or therapeutic antibody.

scholarly journals Antigen-specific immunotherapy with apitopes suppresses generation of FVIII inhibitor antibodies in HLA-transgenic mice

2021 ◽  
Author(s):  
Katrien Pletinckx ◽  
Kirsty S Nicolson ◽  
Heather B Streeter ◽  
William J Sanderson ◽  
Evelien Schurgers ◽  
...  
Keyword(s):  
T Cell ◽  
Replacement Therapy ◽  
Immune Tolerance ◽  
Neutralizing Antibodies ◽  
Antigen Processing ◽  
Specific Immunotherapy ◽  
Tolerance Induction ◽  
Human Leukocyte ◽  
Immunological Tolerance ◽  
Fviii Inhibitor

Haemophilia A (HA) is a blood clotting disorder caused by various genetic deficiencies in the factor VIII (FVIII) encoding F8 gene. Patients receiving FVIII replacement therapy are at risk of developing neutralizing antibodies (FVIII inhibitors) rendering the FVIII replacement therapy ineffective. Immunological tolerance towards FVIII can be achieved through immune tolerance induction (ITI) protocols in some patients but this is a lengthy and costly desensitization programme. Long-term eradication of inhibitors in HA patients could be achieved by antigen-specific immunotherapy targeting CD4+ T cells since formation of FVIII inhibitors is T cell dependent. Here, we report a peptide-based, antigen-specific immunotherapy designed to specifically re-establish immune tolerance to FVIII through the development of antigen-processing-independent epitopes (apitopes). We identified two FVIII immunodominant peptides in immunised human leukocyte antigen (HLA) DRA*0101/DRB1*1501 transgenic (HLA-DR2tg) mice that were optimised for tolerogenicity. These modified peptide analogues were initially screened for recognition using FVIII-specific T cell hybridoma clones from FVIII-immunised HLA-DR2tg mice. The FVIII apitopes were promiscuous and bound common human HLA-DRB1*haplotypes. The combination of these two FVIII apitopes (ATX-F8-117), administered according to a dose escalation protocol, promoted T cell tolerance towards FVIII in HLA-DR2tg mice. Furthermore, treatment with ATX-F8-117 significantly reduced FVIII inhibitor formation. ATX-F8-117 regulates both anti-FVIII T cell and B cell responses, specifically the generation of FVIII inhibitors, revealing peptide-based antigen-specific immunotherapy as a promising approach to both suppress and treat inhibitor formation in susceptible HA patients.

scholarly journals Endogenous Presentation of CD8+ T Cell Epitopes from Epstein-Barr Virus–encoded Nuclear Antigen 1

2004 ◽  
Vol 199 (10) ◽  
pp. 1421-1431 ◽  
Author(s):  
Judy Tellam ◽  
Geoff Connolly ◽  
Katherine J. Green ◽  
John J. Miles ◽  
Denis J. Moss ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Antigen Processing ◽  
Epstein Barr Virus ◽  
Cd8 T Cell ◽  
Nuclear Antigen ◽  
T Cell Epitopes ◽  
Barr Virus ◽  
Degradation Rates ◽  
Epstein Barr

Epstein-Barr virus (EBV)–encoded nuclear antigen (EBNA)1 is thought to escape cytotoxic T lymphocyte (CTL) recognition through either self-inhibition of synthesis or by blockade of proteasomal degradation by the glycine-alanine repeat (GAr) domain. Here we show that EBNA1 has a remarkably varied cell type–dependent stability. However, these different degradation rates do not correspond to the level of major histocompatibility complex class I–restricted presentation of EBNA1 epitopes. In spite of the highly stable expression of EBNA1 in B cells, CTL epitopes derived from this protein are efficiently processed and presented to CD8+ T cells. Furthermore, we show that EBV-infected B cells can readily activate EBNA1-specific memory T cell responses from healthy virus carriers. Functional assays revealed that processing of these EBNA1 epitopes is proteasome and transporter associated with antigen processing dependent. We also show that the endogenous presentation of these epitopes is dependent on the newly synthesized protein rather than the long-lived stable EBNA1. Based on these observations, we propose that defective ribosomal products, not the full-length antigen, are the primary source of endogenously processed CD8+ T cell epitopes from EBNA1.

scholarly journals Progress toward inducing immunologic tolerance to factor VIII

Blood ◽  
2013 ◽  
Vol 121 (22) ◽  
pp. 4449-4456 ◽  
Author(s):  
David W. Scott ◽  
Kathleen P. Pratt ◽  
Carol H. Miao
Keyword(s):  
Animal Model ◽  
T Cell ◽  
Factor Viii ◽  
Immune Tolerance ◽  
High Titer ◽  
Tolerance Induction ◽  
T Cell Epitopes ◽  
Clinical Method ◽  
Model Studies ◽  
Human T Cell

Abstract A major problem in treating hemophilia A patients with therapeutic factor VIII (FVIII) is that 20% to 30% of these patients produce neutralizing anti-FVIII antibodies. These antibodies block (inhibit) the procoagulant function of FVIII and thus are termed “inhibitors.” The currently accepted clinical method to attempt to eliminate inhibitors is immune tolerance induction (ITI) via a protocol requiring intensive FVIII treatment until inhibitor titers drop. Although often successful, ITI is extremely costly and is less likely to succeed in patients with high-titer inhibitors. During the past decade, significant progress has been made in clarifying mechanisms of allo- and autoimmune responses to FVIII and in suppression of these responses. Animal model studies are suggesting novel, less costly methods to induce tolerance to FVIII. Complementary studies of anti-FVIII T-cell responses using blood samples from human donors are identifying immunodominant T-cell epitopes in FVIII and possible targets for tolerogenic efforts. Mechanistic experiments using human T-cell clones and lines are providing a clinically relevant counterpoint to the animal model studies. This review highlights recent progress toward the related goals of lowering the incidence of anti-FVIII immune responses and promoting durable, functional immune tolerance to FVIII in patients with an existing inhibitor.

scholarly journals Suppressive effect of antibody on processing of T cell epitopes.

1993 ◽  
Vol 178 (4) ◽  
pp. 1459-1463 ◽  
Author(s):  
C Watts ◽  
A Lanzavecchia
Keyword(s):  
T Cell ◽  
Antigen Processing ◽  
Suppressive Effect ◽  
T Cell Epitopes ◽  
Strong Suppression ◽  
Lysosomal Ph ◽  
Mhc Molecules ◽  
Class Ii Mhc ◽  
Formed Part ◽  
Antigen Presenting

Immunoglobulins drive efficient antigen capture by antigen presenting cells for processing and presentation on class II MHC-molecules. High affinity antibody/antigen interactions are stable at endosomal/lysosomal pH thus altering the substrate for antigen processing. We show that this can result in strong suppression of presentation of some T cell epitopes. This effect was observed when the antibody specificity was a B cell surface Ig, or formed part of an immune complex. In the latter case the presence of the suppressing antibody boosts presentation of other T cell epitopes through enhanced uptake into Fc receptor bearing cells. The influence of bound antibodies on the outcome of antigen processing may influence with T cell epitopes dominate T cell responses and may change the focus of the response with time.

Induction of Immunological Tolerance to Islet Allografts

1996 ◽  
Vol 5 (1) ◽  
pp. 49-52 ◽  
Author(s):  
Aldo A. Rossini ◽  
David C. Parker ◽  
Nancy E. Phillips ◽  
Fiona H. Durie ◽  
Randolph J. Noelle ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
B Cells ◽  
Tolerance Induction ◽  
Immunological Tolerance ◽  
Splenic Lymphocytes ◽  
Allograft Survival ◽  
Spleen Cells ◽  
Islet Allografts ◽  
Dose Dependent

T-cell dependent activation of resting B cells involves the interaction of gp39 on T cells with its receptor, CD40, on B cells. We administered either a combination of T-cell-depleted splenic lymphocytes and anti-gp39 monoclonal antibody or antibody alone to establish islet allografts in mice without continuous immunosuppression. Fully allogeneic H-2q FVB islets were permanently accepted by chemically diabetic H-2b C57BL/6 mice provided that the recipients were pretreated with both T-cell-depleted donor spleen cells and anti-gp39 antibody. Antibody alone was less effective in prolonging allograft survival, but we did observe that anti-gp39 mAb alone can exert an independent, primary effect on islet allograft survival that was dose dependent. Targeting gp39, in combination with lymphocyte transfusion, might prove suitable for tolerance induction and allotransplantation without immunosuppression.

scholarly journals IMMUNOLOGICAL TOLERANCE IN BONE MARROW-DERIVED LYMPHOCYTES

1974 ◽  
Vol 139 (6) ◽  
pp. 1464-1472 ◽  
Author(s):  
David H. Katz ◽  
Toshiyuki Hamaoka ◽  
Baruj Benacerraf
Keyword(s):  
T Cell ◽  
B Cells ◽  
Cell Function ◽  
Critical Role ◽  
Tolerance Induction ◽  
Immunological Tolerance ◽  
Antigenic Determinants ◽  
Humoral Responses

The present studies were designed to probe the role(s) of T cells in preventing or altering tolerance induction in hapten-specific B cells. This was accomplished by using hapten conjugates of normally immunogenic heterologous carriers to selectively inhibit 2,4-dinitrophenyl (DNP)-primed B cells in adoptive transfer experiments in vivo. The data provide strong indications that one critical role of T-cell participation in humoral responses to antigens is to circumvent the development of a tolerogenic signal that, in the absence of such T-cell function, might otherwise ensue after binding of the antigenic determinants by specific precursor B lymphocytes.

scholarly journals Glycan-regulated Antigen Processing of a Protein in the Endoplasmic Reticulum Can Uncover Cryptic Cytotoxic T Cell Epitopes

1998 ◽  
Vol 188 (4) ◽  
pp. 773-778 ◽  
Author(s):  
Philip Wood ◽  
Tim Elliott
Keyword(s):  
Endoplasmic Reticulum ◽  
T Cell ◽  
T Lymphocyte ◽  
Influenza A ◽  
Antigen Processing ◽  
Secretory Pathway ◽  
Cytotoxic T Lymphocyte ◽  
Cytotoxic T Cell ◽  
T Cell Epitopes ◽  
Ctl Epitopes

We and others have shown that influenza A nucleoprotein (NP) targeted to the secretory pathway cannot be processed to yield several cytotoxic T lymphocyte (CTL) epitopes in cell lines that lack the transporter associated with antigen processing (TAP). However, a large COOH-terminal fragment of NP is processed and presented in these cells. Full-length NP is cotranslationally glycosylated in the lumen of the endoplasmic reticulum at two sites distal to the major H2-Kk and H2-Db restricted CTL epitopes, and we show here that pharmacological or genetic inhibition of N-linked glycosylation, leads to the processing and presentation of both these epitopes in a TAP-independent way.

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