scholarly journals Tissue-specific tolerance in fatal Covid-19

2020 ◽  
Author(s):  
David A Dorward ◽  
Clark D Russell ◽  
In Hwa Um ◽  
Mustafa Elshani ◽  
Stuart D Armstrong ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Reticuloendothelial System ◽  
Lymphoid Tissues ◽  
Therapeutic Approaches ◽  
Tissue Specific ◽  
Cell Responses ◽  
Enhanced Resistance ◽  
Organ Specific ◽  
Reactive Plasmacytosis ◽  
Specific Tolerance

Successful host defence against a pathogen can involve resistance or tolerance, with implications for prioritising either antimicrobial or immunomodulatory therapeutic approaches. Hyper-inflammation occurs in Covid-19 and is associated with worse outcomes. The efficacy of dexamethasone in preventing mortality in critical Covid-19 suggests that inflammation has a causal role in death. Whether this deleterious inflammation is primarily a direct response to the presence of SARS-CoV-2 requiring enhanced resistance, or an independent immunopathologic process necessitating enhanced tolerance, is unknown. Here we report an aberrant immune response in fatal Covid-19, principally involving the lung and reticuloendothelial system, that is not clearly topologically associated with the virus, indicating tissue-specific tolerance of SARS-CoV-2. We found that inflammation and organ dysfunction in fatal Covid-19 did not map to the widespread tissue and cellular distribution of SARS-CoV-2 RNA and protein, both between and within tissues. A monocyte/myeloid-rich vasculitis was identified in the lung, along with an influx of macrophages/monocytes into the parenchyma. In addition, stereotyped abnormal reticulo-endothelial responses (reactive plasmacytosis and iron-laden macrophages) were present and dissociated from the presence of virus in lymphoid tissues. Our results support virus-independent immunopathology being one of the primary mechanisms underlying fatal Covid-19. This supports prioritising pathogen tolerance as a therapeutic strategy in Covid-19, by better understanding non-injurious organ-specific viral tolerance mechanisms and targeting aberrant macrophage and plasma cell responses.

I. Mucosal dendritic cells: their specialized role in initiating T cell responses

1999 ◽  
Vol 276 (5) ◽  
pp. G1074-G1078 ◽  
Author(s):  
Akiko Iwasaki ◽  
Brian L. Kelsall
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Antigen Presenting Cells ◽  
Lymphoid Tissues ◽  
Tissue Specific ◽  
Functional Studies ◽  
Cell Responses ◽  
And Function ◽  
Antigen Presenting

Dendritic cells (DCs) are the most competent antigen-presenting cells known for the induction of primary T cell responses. Functional studies of tissue-resident DCs have been impaired by the rarity of these cells in any given organ. Recent development of isolation procedures allowing extraction of highly purified fresh DC populations has made it possible to study mucosal DCs in distinct mucosa-associated lymphoid tissues. Here, we discuss several recent studies by us and others that describe the tissue-specific phenotype and function of mucosal DCs and speculate on the mechanism by which the resident DCs regulate tissue-specific T cell responses.

scholarly journals Evolutionary conservation of tissue-specific lymphocyte-endothelial cell recognition mechanisms involved in lymphocyte homing.

1988 ◽  
Vol 107 (5) ◽  
pp. 1845-1851 ◽  
Author(s):  
N W Wu ◽  
S Jalkanen ◽  
P R Streeter ◽  
E C Butcher
Keyword(s):  
Lymph Node ◽  
Endothelial Cell ◽  
Human Lymphocytes ◽  
Lymphoid Tissues ◽  
Cell Recognition ◽  
Peripheral Lymph Node ◽  
Lymphocyte Homing ◽  
Tissue Specific ◽  
Peripheral Lymph ◽  
Organ Specific

Tissue-specific interactions with specialized high endothelial venules (HEV) direct the homing of lymphocytes from the blood into peripheral lymph nodes, mucosal lymphoid organs, and tissue sites of chronic inflammation. These interactions have been demonstrated in all mammalian species examined and thus appear highly conserved. To assess the degree of evolutionary divergence in lymphocyte-HEV recognition mechanisms, we have studied the ability of lymphocytes to interact with HEV across species barriers. By using an in vitro assay of lymphocyte binding to HEV in frozen sections of lymphoid tissues, we confirm that mouse, guinea pig, and human lymphocytes bind to xenogeneic as well as homologous HEV. In addition, we show that mouse and human lymphoid cell lines that bind selectively to either peripheral lymph node or mucosal vessels (Peyer's patches, appendix) in homologous lymphoid tissues exhibit the same organ specificity in binding to xenogeneic HEV. Furthermore, monoclonal antibodies that recognize lymphocyte "homing receptors" and block homologous lymphocyte binding to peripheral lymph node or to mucosal HEV, also inhibit lymphocyte interactions with xenogeneic HEV in a tissue-specific fashion. Similarly, anti-HEV antibodies against organ-specific mouse high endothelial cell "addressins" involved in lymphocyte homing to peripheral lymph node or mucosal lymphoid organs, not only block the adhesion of mouse lymphocytes but also of human lymphocytes to target mouse HEV. The results illustrate a remarkable degree of functional conservation of elements mediating these cell-cell recognition events involved in organ-specific lymphocyte homing.

scholarly journals Chronic Inflammation and Radiation-Induced Cystitis: Molecular Background and Therapeutic Perspectives

Cells ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 21
Author(s):  
Carole Helissey ◽  
Sophie Cavallero ◽  
Clément Brossard ◽  
Marie Dusaud ◽  
Cyrus Chargari ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Therapeutic Strategy ◽  
Randomized Trials ◽  
Clinical Presentation ◽  
Therapeutic Approaches ◽  
Radiation Cystitis ◽  
Fibrotic Process ◽  
Radiation Induced ◽  
Therapeutic Irradiation ◽  
Underlying Pathophysiology

Radiation cystitis is a potential complication following the therapeutic irradiation of pelvic cancers. Its clinical management remains unclear, and few preclinical data are available on its underlying pathophysiology. The therapeutic strategy is difficult to establish because few prospective and randomized trials are available. In this review, we report on the clinical presentation and pathophysiology of radiation cystitis. Then we discuss potential therapeutic approaches, with a focus on the immunopathological processes underlying the onset of radiation cystitis, including the fibrotic process. Potential therapeutic avenues for therapeutic modulation will be highlighted, with a focus on the interaction between mesenchymal stromal cells and macrophages for the prevention and treatment of radiation cystitis.

scholarly journals Rituximab Therapy Reduces Organ-Specific T Cell Responses and Ameliorates Experimental Autoimmune Encephalomyelitis

PLoS ONE ◽  
2011 ◽  
Vol 6 (2) ◽  
pp. e17103 ◽  
Author(s):  
Nancy L. Monson ◽  
Petra Cravens ◽  
Rehana Hussain ◽  
Christopher T. Harp ◽  
Matthew Cummings ◽  
...  
Keyword(s):  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
T Cell Responses ◽  
Autoimmune Encephalomyelitis ◽  
Cell Responses ◽  
Organ Specific ◽  
Experimental Autoimmune

In vivo function of regulatory DNA sequence elements of a major histocompatibility complex class I gene

1992 ◽  
Vol 12 (7) ◽  
pp. 3078-3086
Author(s):  
J E Maguire ◽  
W I Frels ◽  
J C Richardson ◽  
J D Weissman ◽  
D S Singer
Keyword(s):  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Regulatory Element ◽  
Class I ◽  
Lymphoid Tissues ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Enhancer Activity ◽  
Tissue Specific ◽  
Histocompatibility Complex

Major histocompatibility complex class I genes are expressed in nearly all somatic tissues, although their level of expression varies. By analysis of a set of promoter deletion mutants introduced into transgenic mice, a complex regulatory element, consisting of overlapping enhancer and silencer activities, is demonstrated to function as a tissue-specific regulator of class I expression. The enhancer activity predominates in lymphoid tissues but not in nonlymphoid tissues. In contrast to the tissue-specific functions of the complex regulatory element, a second novel silencer element is shown to function in both lymphoid and nonlymphoid tissues. The complement of DNA-binding factors in different cell lines is shown to correlate with the levels of class I expression.

scholarly journals 583 Exploring the potential of T cell acute lymphoblastic leukemia (T-ALL) for generating leukemia-specific T cell responses that can be therapeutically harnessed with immunotherapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A613-A613
Author(s):  
Todd Triplett ◽  
Joshua Rios ◽  
Alexander Somma ◽  
Sarah Church ◽  
Khrystyna North ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Systemic Disease ◽  
Flow Cytometric Analysis ◽  
T Cell Responses ◽  
Lymphoid Tissues ◽  
Cell Responses ◽  
Cell Acute Lymphoblastic Leukemia

BackgroundT cell Acute Lymphoblastic Leukemia (T-ALL) is a devastating malignancy found primarily in pediatric populations. Unfortunately, standard of care for T-ALL has not progressed from highly toxic, intensive regimens of chemotherapy, which fails to cure all patients. Immunotherapies designed to activate patients‘ leukemia-specific T cells may provide a new therapeutic avenue to increase complete response rates, reduce toxicity without the need to engineer (e.g. CAR) cells. However, it is unknown whether T-ALL is capable of being recognized by T cells due given its relatively low mutation-rate. These studies therefore sought to investigate whether signs of leukemia-specific T cell responses are generated by T-ALL. Because T-ALL results in systemic disease and infiltrates multiple lymphoid and non-lymphoid tissues, these studies also determined how the divergent immune contextures of these TMEs impacts T cell responses to T-ALL. From this, we aim to identify immunotherapeutic targets capable of activating T cells across tissues to eradicate leukemia systemically.MethodsPrimary leukemia cells isolated from a spontaneous murine model (LN3 mice) into immune-competent, congenic (CD45.1) recipient mice. Tissues were harvested at distinct stages of disease for analysis by flow cytometry or utilizing NanoString Technologies’ GeoMX Digital Spatial Profiling (DSP) platform.ResultsFlow cytometric analysis of T cells revealed extensive changes in response to T-ALL that included multiple features of exhaustion typically associated with anti-tumor responses as determined by upregulation of co-inhibitory receptors and TOX. This included a surprisingly high-frequency of PD1+ T cells, which was accompanied by PDL1- and PDL2-expressing myeloid cells that likely are restraining these subsets. Importantly, combination immunotherapy with OX40 agonists while inhibiting PD1 resulted in drastically reduced tumor burden and concomitant expansion of proliferating granzyme-expressing CD8 T cells. To gain better insight into T cell responses within distinct organs, we analyzed tissue sections using DSP. This technique enabled us to evaluate T cells in direct contact with leukemia infiltrates compared to T cells in regions without T-ALL, which further revealed an enrichment of activated subsets. Importantly, these studies have provided critical insight needed to better understand how T cells responding to T-ALL diverge between distinct types of tissues.ConclusionsThe results from these studies collectively suggest that T cells are activated by T-ALL and that they can be therapeutically harnessed despite relatively low mutation-rates. Future studies will continue analysis of individual organs and use these results to rationally design combinations of immunotherapies by tailoring to activate T cells in all tissue types.AcknowledgementsSpecial thanks to all the support and analysis from everyone at NanoString, along with financial support provided by a SITC-NanoString DSP Fellowship awarded to Dr. Todd Triplett used for DSP analysis of all frozen tissues in these studies. Salary support for Dr. Triplett and pilot funding was provided by departmental funds via a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar Award (Grant #RR160093; awarded to Dr. Gail Eckhardt).

scholarly journals Future of Solid Organ Transplantation: Organ-Specific Tolerance

KIDNEYS ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 130-136
Author(s):  
Yusuf Ercin Sonmez
Keyword(s):  
Immune System ◽  
Solid Organ Transplantation ◽  
Organ Transplant ◽  
Immunological Tolerance ◽  
The Body ◽  
Solid Organ ◽  
Donor Organ ◽  
Organ Specific ◽  
Specific Tolerance

A transplant between two people who are not genetically identical is called an allotransplant and the process is called allotransplantation. Donor organs and tissues can be from people who are living, or people who have died because of a significant brain injury or lack of circulation. Allotransplantation can create a rejection process where the immune system of the recipient attacks the foreign donor organ or tissue and destroys it. The recipient may need to take immunosuppressive medication for the rest of their life to reduce the risk of rejection of the donated organ. In general, deliberately induced immunosuppression is performed to prevent the body from rejecting an organ transplant. The adverse effects associated with these agents and the risks of long-term immunosuppression present a number of challenges for the clinician. Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune response in a given organism.

scholarly journals Atlas of Age- and Tissue-specific DNA Methylation during Early Development of Barley (Hordeum vulgare)

2018 ◽  
Author(s):  
Moumouni Konate ◽  
Michael J. Wilkinson ◽  
Banjamin Mayne ◽  
Eileen Scott ◽  
Bettina Berger ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Hordeum Vulgare ◽  
Organ Function ◽  
Tissue Specific ◽  
Organ Differentiation ◽  
Differentiated Cells ◽  
Differentially Methylated Genes ◽  
Organ Specific ◽  
Development And Differentiation ◽  
Methylation Patterns

The barley (Hordeum vulgare) genome comprises over 32,000 genes, with differentiated cells expressing only a subset of genes; the remainder being silent. Mechanisms by which tissue-specific genes are regulated are not entirely understood, although DNA methylation is likely to be involved. DNA methylation patterns are not static during plant development, but it is still unclear whether different organs possess distinct methylation profiles. Methylation-sensitive GBS was used to generate DNA methylation profiles for roots, leaf-blades and leaf-sheaths from five barley varieties, using seedlings at the three-leaf stage. Differentially Methylated Markers (DMMs) were characterised by pairwise comparisons of roots, leaf-blades and leaf-sheaths of three different ages. While very many DMMs were found between roots and leaf parts, only a few existed between leaf-blades and leaf-sheaths, with differences decreasing with leaf rank. Organ-specific DMMs appeared to target mainly repeat regions, implying that organ differentiation partially relies on the spreading of DNA methylation from repeats to promoters of adjacent genes. Furthermore, the biological functions of differentially methylated genes in the different organs correlated with functional specialisation. Our results indicate that different organs do possess diagnostic methylation profiles and suggest that DNA methylation is important for both tissue development and differentiation and organ function.

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