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  1. Article ; Online: The immunobiology of SARS-CoV-2 infection and vaccine responses: potential influences of cross-reactive memory responses and aging on efficacy and off-target effects.

    Collins, Craig P / Longo, Dan L / Murphy, William J

    Frontiers in immunology

    2024  Volume 15, Page(s) 1345499

    Abstract: Immune responses to both SARS-CoV-2 infection and its associated vaccines have been highly variable within the general population. The increasing evidence of long-lasting symptoms after resolution of infection, called post-acute sequelae of COVID-19 ( ... ...

    Abstract Immune responses to both SARS-CoV-2 infection and its associated vaccines have been highly variable within the general population. The increasing evidence of long-lasting symptoms after resolution of infection, called post-acute sequelae of COVID-19 (PASC) or "Long COVID," suggests that immune-mediated mechanisms are at play. Closely related endemic common human coronaviruses (hCoV) can induce pre-existing and potentially cross-reactive immunity, which can then affect primary SARS-CoV-2 infection, as well as vaccination responses. The influence of pre-existing immunity from these hCoVs, as well as responses generated from original CoV2 strains or vaccines on the development of new high-affinity responses to CoV2 antigenic viral variants, needs to be better understood given the need for continuous vaccine adaptation and application in the population. Due in part to thymic involution, normal aging is associated with reduced naïve T cell compartments and impaired primary antigen responsiveness, resulting in a reliance on the pre-existing cross-reactive memory cell pool which may be of lower affinity, restricted in diversity, or of shorter duration. These effects can also be mediated by the presence of down-regulatory anti-idiotype responses which also increase in aging. Given the tremendous heterogeneity of clinical data, utilization of preclinical models offers the greatest ability to assess immune responses under a controlled setting. These models should now involve prior antigen/viral exposure combined with incorporation of modifying factors such as age on immune responses and effects. This will also allow for mechanistic dissection and understanding of the different immune pathways involved in both SARS-CoV-2 pathogen and potential vaccine responses over time and how pre-existing memory responses, including potential anti-idiotype responses, can affect efficacy as well as potential off-target effects in different tissues as well as modeling PASC.
    MeSH term(s) Humans ; COVID-19 ; Post-Acute COVID-19 Syndrome ; SARS-CoV-2 ; Vaccines ; Aging ; Immunoglobulin Idiotypes
    Chemical Substances Vaccines ; Immunoglobulin Idiotypes
    Language English
    Publishing date 2024-02-26
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2024.1345499
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Potential role of anti-Idiotype responses on the neurological effects of post-acute sequelae of COVID-19 (PASC).

    Murphy, William J / Collins, Craig P / Ashwood, Paul

    Brain, behavior, and immunity

    2023  Volume 116, Page(s) 317–320

    MeSH term(s) Humans ; COVID-19 ; Post-Acute COVID-19 Syndrome ; Disease Progression
    Language English
    Publishing date 2023-12-18
    Publishing country Netherlands
    Document type Journal Article ; Review
    ZDB-ID 639219-2
    ISSN 1090-2139 ; 0889-1591
    ISSN (online) 1090-2139
    ISSN 0889-1591
    DOI 10.1016/j.bbi.2023.12.017
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Suppressive effects of obesity on NK cells: is it time to incorporate obesity as a clinical variable for NK cell-based cancer immunotherapy regimens?

    Canter, Robert J / Judge, Sean J / Collins, Craig P / Yoon, Daniel Jaeho / Murphy, William J

    Journal for immunotherapy of cancer

    2024  Volume 12, Issue 3

    MeSH term(s) Humans ; Killer Cells, Natural ; Immunotherapy ; Neoplasms/therapy ; Obesity/therapy
    Language English
    Publishing date 2024-03-13
    Publishing country England
    Document type Journal Article
    ZDB-ID 2719863-7
    ISSN 2051-1426 ; 2051-1426
    ISSN (online) 2051-1426
    ISSN 2051-1426
    DOI 10.1136/jitc-2023-008443
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Aging augments obesity-induced thymic involution and peripheral T cell exhaustion altering the "obesity paradox".

    Vick, Logan V / Collins, Craig P / Khuat, Lam T / Wang, Ziming / Dunai, Cordelia / Aguilar, Ethan G / Stoffel, Kevin / Yendamuri, Sai / Smith, Randall / Mukherjee, Sarbajit / Barbi, Joseph / Canter, Robert J / Monjazeb, Arta M / Murphy, William J

    Frontiers in immunology

    2023  Volume 13, Page(s) 1012016

    Abstract: Introduction: The incidence of obesity, a condition characterized by systemic chronic inflammation, has reached pandemic proportions and is a poor prognostic factor in many pathologic states. However, its role on immune parameters has been diverse and ... ...

    Abstract Introduction: The incidence of obesity, a condition characterized by systemic chronic inflammation, has reached pandemic proportions and is a poor prognostic factor in many pathologic states. However, its role on immune parameters has been diverse and at times contradictory. We have previously demonstrated that obesity can result in what has been called the "obesity paradox" which results in increased T cell exhaustion, but also greater efficacy of immune checkpoint blockade in cancer treatment.
    Methods: The role of obesity, particularly in the context of aging, has not been robustly explored using preclinical models. We therefore evaluated how age impacts the immune environment on T cell development and function using diet-induced obese (DIO) mice.
    Results: We observed that DIO mice initially displayed greater thymopoiesis but then developed greater thymic involution over time compared to their lean counterparts. Both aging and obesity resulted in increased T cell memory conversion combined with increased expression of T cell exhaustion markers and Treg expansion. This increased T cell immunosuppression with age then resulted in a loss of anti-tumor efficacy by immune checkpoint inhibitors (ICIs) in older DIO mice compared to the younger DIO counterparts.
    Discussion: These results suggest that both aging and obesity contribute to T cell dysfunction resulting in increased thymic involution. This combined with increased T cell exhaustion and immunosuppressive parameters affects immunotherapy efficacy reducing the advantage of obesity in cancer immunotherapy responses.
    MeSH term(s) Mice ; Animals ; Thymus Gland ; T-Cell Exhaustion ; Aging ; Obesity ; Cell Differentiation ; Mice, Obese
    Language English
    Publishing date 2023-01-26
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2022.1012016
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Activation status dictates the function of unlicensed natural killer cells in mice and humans.

    Aguilar, Ethan G / Dunai, Cordelia / Judge, Sean J / Zamora, Anthony E / Khuat, Lam T / Vick, Logan V / Collins, Craig P / Stoffel, Kevin M / Alvarez, Maite / Barao, Isabel / Miller, Jeffrey S / Blazar, Bruce R / Chevallier, Patrice / Retiere, Christelle / Canter, Robert J / Murphy, William J

    Blood advances

    2021  Volume 5, Issue 20, Page(s) 4219–4232

    Abstract: Natural killer (NK) cells are involved in innate defense against viral infection and cancer. NK cells can be divided into subsets based on the ability of different receptors to bind to major histocompatibility (MHC) class 1 molecules, resulting in ... ...

    Abstract Natural killer (NK) cells are involved in innate defense against viral infection and cancer. NK cells can be divided into subsets based on the ability of different receptors to bind to major histocompatibility (MHC) class 1 molecules, resulting in differential responses upon activation in a process called "licensing" or "arming." NK cells expressing receptors that bind self-MHC are considered licensed due to an augmented effector lytic function capability compared with unlicensed subsets. However, we demonstrated that unlicensed NK subsets instead positively regulate the adaptive T-cell response during viral infections that are related to localization and cytokine production. In this study, the differential effects of the two types of NK subsets were contingent on the environment in viral infection and hematopoietic stem cell transplantation (HSCT) models. Infection of mice with high-dose (HD) murine cytomegalovirus (MCMC) led to a loss of licensing-associated differences, as compared with mice with low-dose (LD) infection: the unlicensed NK subset no longer localized in lymph nodes (LNs), but instead remained at the site of infection. Similarly, the patterns observed during HD infection paralleled the phenotypes of both human and mouse NK cells in an HSCT setting where NK cells exhibit an activated phenotype. However, in contrast to the effects of subset depletion in T-cell replete models, the licensed NK cell subsets still dominated antiviral responses after HSCT. Overall, our results highlight the intricate tuning of NK cells and how it affects overall immune responses with regard to licensing patterns and their dependency on the level of stimulation and activation status.
    MeSH term(s) Animals ; Hematopoietic Stem Cell Transplantation ; Humans ; Killer Cells, Natural ; Mice ; Mice, Inbred C57BL ; Muromegalovirus
    Language English
    Publishing date 2021-09-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2915908-8
    ISSN 2473-9537 ; 2473-9529
    ISSN (online) 2473-9537
    ISSN 2473-9529
    DOI 10.1182/bloodadvances.2021004589
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Increased efficacy of dual proinflammatory cytokine blockade on acute GVHD while maintaining GVT effects.

    Khuat, Lam T / Vick, Logan V / Dunai, Cordelia / Collins, Craig P / More, Shyam K / Le, Catherine T / Pai, Chien-Chun Steven / Stoffel, Kevin M / Maverakis, Emanual / Canter, Robert J / Monjazeb, Arta M / Longo, Dan L / Abedi, Mehrdad / Choi, Eunju / Blazar, Bruce R / Dave, Maneesh / Murphy, William J

    Blood

    2021  Volume 138, Issue 24, Page(s) 2583–2588

    Abstract: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a potential curative option for treating a variety of hematologic diseases, but acute and chronic graft-versus-host disease (GVHD) remain major barriers limiting efficacy. Acute gut ... ...

    Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a potential curative option for treating a variety of hematologic diseases, but acute and chronic graft-versus-host disease (GVHD) remain major barriers limiting efficacy. Acute gut GVHD occurs with marked increases in proinflammatory cytokines (including TNF and IL-6), which we recently demonstrated was exacerbated in obesity resulting in severe gastrointestinal pathology. Given the pleiotropic and overlapping effects of these 2 cytokines, we assessed the impact of dual TNF and IL-6R blockade on GVHD as well as graft-versus tumor (GVT) effects in different mouse GVHD models. Early administration of combined blockade resulted in greater protection and survival from acute gut GVHD compared with single blockade regimens and even development of later chronic skin GVHD. Importantly, double cytokine blockade preserved GVT effects reinforcing that GVT and GVHD can be delineated and may result in greater efficacy in allo-HSCT.
    MeSH term(s) Animals ; Anti-Inflammatory Agents/therapeutic use ; Antibodies, Monoclonal/therapeutic use ; Disease Models, Animal ; Etanercept/therapeutic use ; Female ; Graft vs Host Disease/prevention & control ; Graft vs Tumor Effect/drug effects ; Hematopoietic Stem Cell Transplantation/methods ; Humans ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Receptors, Interleukin-6/antagonists & inhibitors ; Transplantation, Homologous/methods ; Tumor Necrosis Factor Inhibitors/therapeutic use ; Mice
    Chemical Substances Anti-Inflammatory Agents ; Antibodies, Monoclonal ; Receptors, Interleukin-6 ; Tumor Necrosis Factor Inhibitors ; Etanercept (OP401G7OJC)
    Language English
    Publishing date 2021-08-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2021011216
    Database MEDical Literature Analysis and Retrieval System OnLINE

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