Engineering antigen-specific immunological tolerance

Kontos, Stephan; Grimm, Alizée J.; Hubbell, Jeffrey A.

doi:10.1016/j.coi.2015.05.005

Cited by 32 publications

(28 citation statements)

References 41 publications

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“…In contrast, prior studies utilizing IFN‐α/β injections to increase antibody responses have reported that IFN‐α/β–mediated responses by cDCs, T cells, and B cells promoted humoral immune responses to soluble antigens . This apparent discrepancy might reflect inherent differences between responses to soluble and RBC‐bound antigens . In addition, although RBC alloimmunization to other antigens requires DC presentation to T cells, it is possible that T cell help is not required for anti‐KEL responses in this model.…”

Section: Discussionmentioning

confidence: 58%

“…The role of IFN‐α/β in RBC alloimmunization has not been previously investigated. In comparison to viral and soluble antigens, RBC‐bound antigens differ in their route of administration, quantity of antigen, duration of exposure, and accessibility to niches within secondary lymphoid tissue . Thus, the role of IFN‐α/β in RBC alloimmunization may differ from their role in autoimmunity, viral infections, or immunization.…”

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confidence: 99%

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B cells require Type 1 interferon to produce alloantibodies to transfused KEL‐expressing red blood cells in mice

Gibb¹,

Liu²,

Santhanakrishnan³

et al. 2017

Transfusion

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Background Alloantibodies to RBC antigens can cause significant hemolytic events. Prior studies have demonstrated that inflammatory stimuli in animal models and inflammatory states in humans, including autoimmunity and viremia, promote alloimmunization. However, molecular mechanisms underlying these findings are poorly understood. Given that type 1 interferons (IFNα/β) regulate antiviral immunity and autoimmune pathology, the hypothesis that IFNα/β regulates RBC alloimmunization was tested in a murine model. Study Design and Methods Leuko-reduced murine RBCs expressing the human KEL glycoprotein were transfused into control mice (WT), mice lacking the unique IFNα/β receptor (IFNAR1−/−), or bone marrow chimeric mice lacking IFNAR1 on specific cell populations. Anti-KEL IgG production, expressed as mean fluorescence intensity (MFI), and B cell differentiation were examined. Results Transfused WT mice produced anti-KEL IgG alloantibodies (peak response MFI=50.4). However, the alloimmune response of IFNAR1−/− mice was almost completely abrogated (MFI=4.2, p<0.05). The response of bone marrow chimeric mice lacking IFNAR1 expression in all hematopoietic cells or specifically in B cells was also diminished (MFI=3.8 and 5.4, respectively, compared to control chimeras, MFI=65.6, p<0.01). Accordingly, transfusion-induced differentiation of IFNAR1−/− B cells into germinal center B cells and plasma cells was significantly reduced, compared to WT B cells. Conclusions This study demonstrates that B cells require signaling from IFNα/β to produce alloantibodies to the human KEL glycoprotein in mice. These findings provide a potential mechanistic basis for inflammation-induced alloimmunization. If these findings extend to human studies, patients with IFNα/β-associated conditions may have an elevated risk of alloimmunization and benefit from personalized transfusion protocols.

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Section: Discussionmentioning

confidence: 58%

mentioning

confidence: 99%

B cells require Type 1 interferon to produce alloantibodies to transfused KEL‐expressing red blood cells in mice

Gibb¹,

Liu²,

Santhanakrishnan³

et al. 2017

Transfusion

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“…[1] When tolerance to self-antigens (e.g. host proteins) is not maintained, inflammation and autoimmune disease can develop.…”

Section: Introductionmentioning

confidence: 99%

“…[11–19] These populations can control self-reactive effector cells (e.g., T H 1, T H 17) that drive autoimmune disease while limiting broad suppression. [1] Expansion and biasing of T cells toward regulatory response also reduces the absolute number of inflammatory cells and offers the potential for more durable treatments. [20, 21]…”

Section: Introductionmentioning

confidence: 99%

Polyplexes assembled from self-peptides and regulatory nucleic acids blunt toll-like receptor signaling to combat autoimmunity

et al. 2017

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Autoimmune diseases occur when the immune system incorrectly recognize self-molecules as foreign; in the case of multiple sclerosis (MS), myelin is attacked. Intriguingly, new studies reveal toll-like receptors (TLR), pathways usually involved in generating immune response again pathogens, play a significant role in driving autoimmune disease in both humans and animal models. We reasoned polyplexes formed from myelin self-antigen and regulatory TLR antagonists might limit TLR signaling during differentiation of myelin-specific T cells, inducing tolerance by biasing T cells away from inflammatory phenotypes. Complexes were formed by modifying myelin peptide with cationic amino acids to create peptides able to condense the anionic nucleic-acid based TLR antagonist. These immunological polyplexes eliminate synthetic polymers commonly used to condense polyplexes and do not rely on gene expression; however, the complexes mimic key features of traditional polyplexes such as tunable loading and co-delivery. Using these materials and classic polyplex analysis techniques, we demonstrate condensation of both immune signals, protection from enzymatic degradation, and tunable physicochemical properties. We show polyplexes reduce TLR-signaling, and in primary DC and T cell co-culture, reduce myelin-driven inflammation. During mouse models of MS, these tolerogenic polyplexes improve the progression, severity, and incidence of disease.

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“…[4,10,11] Thus a variety of different approaches have been pursued to mitigate immunogenicity, including shielding proteins with chemical or biological blocking moieties (e.g., PEGylation,[12,13] XTENylation,[14] PASylation,[15] or reductive methylation[16]), explicitly training the immune system to tolerate proteins,[17] or implicitly rendering proteins tolerable by humanization (with emerging new engineering techniques for antibodies[18-22] as well as non-immunoglobulin proteins[23,24]). In any case, molecular recognition of exogenous proteins by antibodies, antigen presenting cells, and T cells is central to the anti-biotherapeutic immune response, and this review focuses on protein deimmunization by genetic manipulation of immunogenic subsequences, termed “epitopes”.…”

Section: Introductionmentioning

confidence: 99%

Design and engineering of deimmunized biotherapeutics

Griswold

Bailey‐Kellogg

2016

Current Opinion in Structural Biology

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Therapeutic proteins are powerful next-generation drugs able to effectively treat diverse and devastating diseases, but the development and use of biotherapeutics entails unique challenges and risks. In particular, protein drugs are subject to immune surveillance in the human body, and ensuing antidrug immune responses can cause a wide range of problems including altered pharmacokinetics, loss of efficacy, and even life-threating complications. Here we review recent progress in technologies for engineering deimmunized biotherapeutics, placing particular emphasis on deletion of immunogenic antibody and T cell epitopes via experimentally or computationally guided mutagenesis.

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Engineering antigen-specific immunological tolerance

Cited by 32 publications

References 41 publications

B cells require Type 1 interferon to produce alloantibodies to transfused KEL‐expressing red blood cells in mice

B cells require Type 1 interferon to produce alloantibodies to transfused KEL‐expressing red blood cells in mice

Polyplexes assembled from self-peptides and regulatory nucleic acids blunt toll-like receptor signaling to combat autoimmunity

Design and engineering of deimmunized biotherapeutics

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