Anterior chamber associated immune deviation to cytosolic neural antigens avoids self-reactivity after optic nerve injury and polarizes the retinal environment to an anti-inflammatory profile

Martínez-Alcantar, Lorena; Talavera-Carrillo, D.K.; Pineda-Salazar, Jonhatan Uriel; Avalos-Viveros, Miguel; Gutiérrez‐Ospina, Gabriel; Phillips-Farfán, Bryan V.; Fuentes-Farías, A.L.; Meléndez‐Herrera, Esperanza

doi:10.1016/j.jneuroim.2019.05.005

Cited by 4 publications

(4 citation statements)

References 35 publications

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“…Moreover, a phenomenon known as anterior chamber-associated immune deviation (ACAID) has been described in the eye upon recognition of immunogenic antigens, which involves the induction of Tregs, anti-inflammatory M2 macrophages, and the generation of an antiinflammatory cytokine environment that promotes immunological tolerance. 122,123 This pro-tolerogenic environment is a protective adaptation aimed at preventing inflammatory responses that could affect vision. An immune deviation phenomenon similar to ACAID has been reported in the context of AAV vector administration to the subretinal space.…”

Section: Impact and Relevance Of Anti-aav Antibodiesmentioning

confidence: 99%

AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer

2020

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Gene therapy with adeno-associated virus (AAV) vectors has demonstrated safety and long-term efficacy in a number of trials across target organs, including eye, liver, skeletal muscle, and the central nervous system. Since the initial evidence that AAV vectors can elicit capsid T cell responses in humans, which can affect the duration of transgene expression, much progress has been made in understanding and modulating AAV vector immunogenicity. It is now well established that exposure to wild-type AAV results in priming of the immune system against the virus, with development of both humoral and T cell immunity. Aside from the neutralizing effect of antibodies, the impact of pre-existing immunity to AAV on gene transfer is still poorly understood. Herein, we review data emerging from clinical trials across a broad range of gene therapy applications. Common features of immune responses to AAV can be found, suggesting, for example, that vector immunogenicity is dose-dependent, and that innate immunity plays an important role in the outcome of gene transfer. A range of host-specific factors are also likely to be important, and a comprehensive understanding of the mechanisms driving AAV vector immunogenicity in humans will be key to unlocking the full potential of in vivo gene therapy. Pre-existing Immunity to WT AAV in Humans Pre-existing Humoral ImmunitySeveral studies have investigated the seroprevalence of neutralizing antibodies directed against WT AAV in humans. [20][21][22][23][24][25] Seroprevalence varies geographically, with anti-AAV2 neutralizing antibodies displaying the highest prevalence, ranging from 30% to 60% of the population. Due to the broad cross-reactivity between AAV serotypes, 26 neutralizing antibodies recognizing virtually all serotypes can be found in almost all subjects. 27 This cross-reactivity reflects the amino acid sequence and structural homology across capsids of different AAV serotypes. 28 The prevalence of total anti-AAV antibodies is close to 70% of the population for AAV1 and AAV2, 45% for AAV6 and AAV9, and 38% for AAV8. 20 Importantly, titers of anti-AAV immunoglobulin G (IgG) antibodies correlate significantly with titers of

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Section: Impact and Relevance Of Anti-aav Antibodiesmentioning

confidence: 99%

AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer

2020

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“…These results support the idea that the eyes may indeed prime systemic immune tolerance across the body. In agreement with this conclusion, the sensitization of the eye’s anterior chamber with a variety of antigens offers immunological protection against autoimmune diseases or reduces tissue damage after physical or vascular injury [ 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 ].…”

Section: Discussionmentioning

confidence: 65%

Looking beyond Self-Protection: The Eyes Instruct Systemic Immune Tolerance Early in Life

Villafán,

Gutiérrez-Ospina

2023

Brain Sciences

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The eyes provide themselves with immune tolerance. Frequent skin inflammatory diseases in young blind people suggest, nonetheless, that the eyes instruct a systemic immune tolerance that benefits the whole body. We tested this premise by using delayed skin contact hypersensitivity (DSCH) as a tool to compare the inflammatory response developed by sighted (S) and birth-enucleated (BE) mice against oxazolone or dinitrofluorobenzene at the ages of 10, 30 and 60 days of life. Adult mice enucleated (AE) at 60 days of age were also assessed when they reached 120 days of life. BE mice displayed exacerbated DSCH at 60 but not at 10 or 30 days of age. AE mice, in contrast, show no exacerbated DSCH. Skin inflammation in 60-day-old BE mice was hapten exclusive and supported by distinct CD8+ lymphocytes. The number of intraepidermal T lymphocytes and migrating Langerhans cells was, however, similar between S and BE mice by the age of 60 days. Our observations support the idea that the eyes instruct systemic immune tolerance that benefits organs outside the eyes from an early age. The higher prevalence of inflammatory skin disorders reported in young people might then reflect reduced immune tolerance associated with the impaired functional morphology of the eyes.

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“…Hence, measures aimed at inducing immune tolerance against hooves' mesenchymal tissue may help in preventing such a loss. In this regard, the infusion of mesenchymal antigens obtained from laminitic hooves into the eye's anterior chamber may be a path to investigate in the coming years (51) .…”

Section: Discussionmentioning

confidence: 99%

Tratamiento de la laminitis crónica en equinos utilizando células troncales mesenquimales alogénicas de la médula ósea

García-Lascuráin¹,

Aranda-Contreras

Gomez-Chavarin³

et al. 2021

Rev. Mex. Cienc. Pecu.

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Chronic laminitis is a disabling condition that affects the laminar corium of the horse’s hooves. Commonly, it develops as a collateral injury of numerous primary systemic diseases. It is believed that the critical physiopathological event that renders a hoof laminitic is the loss of mesenchymal stem cells. This loss greatly impairs the ability of the laminar corium to regenerate. Although previous work provides credibility to this notion, there remain unsettled issues that must be addressed before accepting it as a well-founded fact. Here, it was reexamined the central tenet of the physiopathological model of laminitis by infusing allogeneic bone marrow-derived mesenchymal stem cells (ABM-MSCs), through the digital palmar vein, into the hooves of horses afflicted by chronic laminitis. Horses were clinically monitored during 6 mo by evaluating them monthly using the lameness-modified Obel-Glasgow’s scale and hooves thermography. Venograms and lamellar biopsies were taken at the beginning and at the end of the study period to gathered evidence on vascular remodeling and laminar corium regeneration. The results showed that ABM-MSCs infusion promotes vascular remodeling and laminar corium regeneration, further supporting that the loss of stem cells is the critical event leading to chronic laminitis. This work also demonstrated that the infusion of ABM-MSCs is safe since the treated horses did not develop local or systemic, negative clinical manifestations attuned with rejection reactions, at least during the 6-mo period they were follow up and under the therapeutic scheme proposed.

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Anterior chamber associated immune deviation to cytosolic neural antigens avoids self-reactivity after optic nerve injury and polarizes the retinal environment to an anti-inflammatory profile

Cited by 4 publications

References 35 publications

AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer

AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer

Looking beyond Self-Protection: The Eyes Instruct Systemic Immune Tolerance Early in Life

Tratamiento de la laminitis crónica en equinos utilizando células troncales mesenquimales alogénicas de la médula ósea

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