Ubiquitous antigen-specific T regulatory type 1 cells variably suppress hepatic and extrahepatic autoimmunity

Umeshappa, Channakeshava Sokke; Mbongue, Jacques C.; Singha, Santiswarup; Mohapatra, Saswat; Yamanouchi, Jun; Lee, Justin A.; Nanjundappa, Roopa Hebbandi; Shao, Kun; Christen, Urs; Yang, Yang; Ellestad, Kristofor K.; Santamaría, Pere

doi:10.1172/jci130670

Cited by 39 publications

(68 citation statements)

References 12 publications

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“…In both EAE or AIH models, Tr1 cells induced in response to PDC-E2-based pMHCII-NPs (referred to hereafter as PDC-NPs) homed to and accumulated into the target organ and/or proximal draining lymph nodes. 12,13 In mice simultaneously having AIH and EAE, however, these compounds selectively blunted liver autoimmunity. 13 Myelin oligodendrocyte glycoprotein (MOG) is a CNSspecific autoantigen that is used to induce EAE.…”

Section: Introductionmentioning

confidence: 99%

“…12,13 In mice simultaneously having AIH and EAE, however, these compounds selectively blunted liver autoimmunity. 13 Myelin oligodendrocyte glycoprotein (MOG) is a CNSspecific autoantigen that is used to induce EAE. 15 Contrary to experiments using PDC-NPs, treatment of comorbid mice having both AIH and EAE with MOG-based pMHCII-NPs (referred to hereafter as MOG-NPs) triggered the formation and recruitment of cognate Tr1 cells to the CNS-draining lymph nodes, and reversed CNS autoimmunity without suppressing liver inflammation.…”

Section: Introductionmentioning

confidence: 99%

“…In fact, pMHCII-NPs displaying epitopes from ubiquitously expressed autoantigens, including the mitochondrial PDC-E2 complex, can suppress not only a wide range of liver autoimmune diseases, 12 including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis, but also extra-hepatic autoimmunity. 13 Surprisingly, however, when these compounds were used to treat both liver and central nervous system (CNS)-specific autoimmunity simultaneously in co-morbid mice, Tr1-cell recruitment and therapeutic efficacy were skewed towards the liver, in some cases completely sparing the CNS. 13 Mice with either AIH or experimental autoimmune encephalomyelitis (EAE) can be treated effectively with pMHCII-NPs displaying epitopes from PDC-E2.…”

Section: Introductionmentioning

confidence: 99%

“…13 Surprisingly, however, when these compounds were used to treat both liver and central nervous system (CNS)-specific autoimmunity simultaneously in co-morbid mice, Tr1-cell recruitment and therapeutic efficacy were skewed towards the liver, in some cases completely sparing the CNS. 13 Mice with either AIH or experimental autoimmune encephalomyelitis (EAE) can be treated effectively with pMHCII-NPs displaying epitopes from PDC-E2. PDC-E2 was described as a key autoantigen in the development of PBC, 14 though it is a ubiquitous self-antigen located in mitochondria.…”

Section: Introductionmentioning

confidence: 99%

“…15 Contrary to experiments using PDC-NPs, treatment of comorbid mice having both AIH and EAE with MOG-based pMHCII-NPs (referred to hereafter as MOG-NPs) triggered the formation and recruitment of cognate Tr1 cells to the CNS-draining lymph nodes, and reversed CNS autoimmunity without suppressing liver inflammation. 13 However, when these studies were repeated in co-morbid mice having EAE and a more severe form of liver autoimmunity than AIH (namely PBC), the MOG-specific Tr1 cells induced by MOG-NPs also failed to suppress the progression of EAE. 13 Our goal in this study is to explore how interactions between physiological variables of interest, namely Tr1 cells, effector T-cells and APCs, and variations in physiological parameters, including tissue size, Tr1 cell recruitment, retention and accumulation, and local versus systemic autoantigen expression bring about such outcomes.…”

Section: Introductionmentioning

confidence: 99%

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Quantifying immunoregulation by autoantigen‐specific T‐regulatory type 1 cells in mice with simultaneous hepatic and extra‐hepatic autoimmune disorders

2020

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Nanoparticles (NPs) displaying autoimmune disease-relevant peptide-major histocompatibility complex class II molecules (pMHCII-NPs) trigger cognate T-regulatory type 1 (Tr1)-cell formation and expansion, capable of reversing organ-specific autoimmune responses. These pMHCII-NPs that display epitopes from mitochondrial protein can blunt the progression of both autoimmune hepatitis (AIH) and experimental autoimmune encephalomyelitis (EAE) in mice carrying either disease. However, with co-morbid mice having both diseases, these pMHCII-NPs selectively treat AIH. In contrast, pMHCII-NPs displaying central nervous system (CNS)specific epitopes can efficiently treat CNS autoimmunity, both in the absence and presence of AIH, without having any effects on the progression of the latter. Here, we develop a compartmentalized population model of T-cells in co-morbid mice to identify the mechanisms by which Tr1 cells mediate organ-specific immunoregulation. We perform time-series simulations and bifurcation analyses to study how varying physiological parameters, including local cognate antigenic load and rates of Tr1-cell recruitment and retention, affect T-cell allocation and Tr1-mediated immunoregulation. Various regimes of behaviour, including 'competitive autoimmunity' where pMHCII-NP-treatment fails against both diseases, are identified and compared with experimental observations. Our results reveal that a transient delay in Tr1-cell recruitment to the CNS, resulting from inflammation-dependent Tr1-cell allocation, accounts for the livercentric effects of AIH-specific pMHCII-NPs in co-morbid mice as compared with mice exclusively having EAE. They also suggest that cognate autoantigen expression and local Tr1-cell retention are key determinants of effective regulatory-cell function. These results thus provide new insights into the rules that govern Tr1-cell recruitment and their autoregulatory function.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Quantifying immunoregulation by autoantigen‐specific T‐regulatory type 1 cells in mice with simultaneous hepatic and extra‐hepatic autoimmune disorders

2020

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Biomaterial Strategies for Selective Immune Tolerance: Advances and Gaps

2023

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Autoimmunity and allergies affect a large number of people across the globe. Current approaches to these diseases target cell types and pathways that drive disease, but these approaches are not cures and cannot differentiate between healthy cells and disease‐causing cells. New immunotherapies that induce potent and selective antigen‐specific tolerance is a transformative goal of emerging treatments for autoimmunity and serious allergies. These approaches offer the potential of halting—or even reversing—disease, without immunosuppressive side effects. However, translating successful induction of tolerance to patients is unsuccessful. Biomaterials offer strategies to direct and maximize immunological mechanisms of tolerance through unique capabilities such as codelivery of small molecules or signaling molecules, controlling signal density in key immune tissues, and targeting. While a growing body of work in this area demonstrates success in preclinical animal models, these therapies are only recently being evaluated in human trials. This review will highlight the most recent advances in the use of materials to achieve antigen‐specific tolerance and provide commentary on the current state of the clinical development of these technologies.

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Delivery Route Considerations for Designing Antigen‐Specific Biomaterial Strategies to Combat Autoimmunity

Ackun-Farmmer

Jewell

2023

Advanced NanoBiomed Research

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Motivating the Development of Antigen-Specific ImmunotherapiesAutoimmune diseases such as multiple sclerosis (MS), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CD), and many others develop when the immune system mistakenly recognizes self-antigens as foreign, resulting in an orchestrated attack of host tissues. MS is a demyelinating disease that affects the central nervous system (CNS), RA is a chronic inflammatory joint disorder that can affect other tissues and organs, and T1D is a chronic condition whereby the pancreas produces little or no insulin. Complications from T1D can impact other tissues and organs. CD is a chronic digestive autoimmune disease that is triggered by gluten consumption, resulting in damage to the small intestine. The exact causes of autoimmune diseases are only partially understood. However, biological sex, [1,2] genetics, [3,4] existing autoimmune disease, [5] lifestyle (i.e., smoking, obesity, and exposure), [6][7][8][9][10][11] certain medications, [12] and certain infections [13][14][15][16][17] have been linked with the development of autoimmune diseases. For example, most autoimmune diseases affect more female than male patients, but the reason for this bias is unclear. [1] In MS, risk gene variant, HLA-DRB1*15:01, increases risk for patients, [18] and infection by Epstein-Barr virus (EBV) is associated with increased risks of MS, RA, and other autoimmune diseases. [13][14][15] These are currently no cures for these diseases, creating chronic battles that affect patient quality of life and require life-long compliance. Owing to the complex immunopathology of autoimmune disease, current treatments, even monoclonal antibodies, are not able to distinguish between normal and self-reactive cells. These therapies exploit distinct parenteral (e.g., intravenous [IV], subcutaneous [S.C.], intramuscular (IM), intradermal (ID), transdermal, intranodal) or mucosal (e.g., oral, intranasal (IN), pulmonary, sublingual, ocular) delivery routes to reduce disease severity. [19][20][21][22][23] For example, Ocrelizumab (Ocrevus, Genentech), a recombinant antibody that binds to CD20 on B lymphocytes to treat MS, is administered via IV injection and associated with risk of infections and allergic responses in certain patients. [19] Methotrexate, a first-line disease-modifying antirheumatic drug, is provided orally or S.C. but can lead to liver and lung damage and

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Ubiquitous antigen-specific T regulatory type 1 cells variably suppress hepatic and extrahepatic autoimmunity

Cited by 39 publications

References 12 publications

Quantifying immunoregulation by autoantigen‐specific T‐regulatory type 1 cells in mice with simultaneous hepatic and extra‐hepatic autoimmune disorders

Quantifying immunoregulation by autoantigen‐specific T‐regulatory type 1 cells in mice with simultaneous hepatic and extra‐hepatic autoimmune disorders

Biomaterial Strategies for Selective Immune Tolerance: Advances and Gaps

Delivery Route Considerations for Designing Antigen‐Specific Biomaterial Strategies to Combat Autoimmunity

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