Specialized regulatory T cells control venous blood clot resolution through SPARC

Blood ◽  
2020 ◽  
Author(s):  
Fatemeh Shahneh ◽  
Grill Alexandra ◽  
Matthias Klein ◽  
Felix Frauhammer ◽  
Tobias Bopp ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Matrix Metalloproteinase ◽  
Blood Clot ◽  
Venous Blood ◽  
Treg Cells ◽  
Therapeutic Window ◽  
Cysteine Rich Protein ◽  
Treg Population ◽  
Blood Clots

The cells and mechanisms involved in blood clot resorption are only partially known. We show that regulatory T (Treg) cells accumulate in venous blood clots and regulate thrombolysis by controlling the recruitment, differentiation and matrix metalloproteinase (MMP) activity of monocytes. We describe a clot Treg population that forms the matricellular acid- and cysteine-rich protein (SPARC), show that SPARC enhances monocyte MMP activity and that SPARC+ Treg are crucial for blood clot resorption. By comparing different treatment times, we define a therapeutic window of Treg expansion that accelerates clot resorption.

scholarly journals 861 Reprogramming regulatory T cells (Treg) using a MALT1 inhibitor for cancer therapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A902-A902
Author(s):  
Peter Keller ◽  
Irina Mazo ◽  
Yun Gao ◽  
Vijayapal Reddy ◽  
Francisco Caballero ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Solid Tumors ◽  
Immune Checkpoint ◽  
Phase 1 ◽  
Treg Cells ◽  
Cell Killing ◽  
Therapeutic Window ◽  
List Type ◽  
Link Type

BackgroundMALT1 protease is a promising target in aggressive lymphomas1, and two phase 1 clinical trials in hematological cancers are ongoing (NCT03900598, NCT04876092). More recently, MALT1 protease inhibition was also shown to reprogram regulatory T cells (Treg) in solid tumors, causing them to lose their immunosuppressive function and secrete interferon-gamma (IFN).2 Changes in Treg metabolism in the tumor microenvironment (TME) may account for their destabilization and selective susceptibility to reprogramming in tumor tissue.3 4 5 While strong MALT1 inhibition can cause Treg depletion in blood and induce autoimmune toxicity,6 a therapeutic window for a differentiated MALT1 inhibitor that reprograms destabilized Treg in the TME before affecting Treg in healthy tissue may exist.2 MPT-0118 is an orally dosed MALT1 inhibitor developed to reprogram destabilized Treg in the TME without causing autoimmune symptoms. A Phase 1/1b dose-escalation and cohort-expansion clinical trial evaluating MPT-0118 is underway (NCT04859777).MethodsHuman xenograft models of lymphoma were used to assess the direct activity of MPT-0118 on MALT1-dependent (but not not MALT1-independent) hematologic tumors. Effects of MPT-0118 on solid tumors were determined in syngeneic cancer models. Human and mouse tumor tissues were evaluated for Treg reprogramming by in situ hybridization or flow cytometry. Patient-derived organotypic tumor spheroids were assessed for immune-mediated cell killing. Studies in rodents and dogs assessed pharmacokinetics (PK) and safety.ResultsMPT-0118 was selective and effective in preventing growth of aggressive MALT1 protease-dependent lymphomas. Beyond direct activity on hematologic malignancies, MPT-0118 also increased anti-tumor immune responses as single-agent or in combination with anti-PD-1 in syngeneic tumor models that are otherwise unresponsive to immune checkpoint blockade (ICB). MPT-0118-treated syngeneic tumors showed an increase in IFN-secreting Treg, associated with decelerated tumor growth. PK studies reveal that MPT-0118 has a high volume of distribution, and effective inhibitor concentrations are reached in the murine tumors upon oral dosing. The drug candidate caused tumor-associated Treg to produce IFN without changing the frequency of Treg circulating in the blood. Ex vivo, MPT-0118 induced Treg reprogramming in tumors resected from patients with colorectal and endometrial cancers and cell killing in spheroids derived from patients with colorectal cancer.ConclusionsThe MALT1 inhibitor MPT-0118 is a clinical candidate for treating MALT1-expressing lymphomas and Treg-infiltrated solid tumors. MPT-0118 exploits the therapeutic opportunity presented by destabilized Treg in the TME. Treg reprogramming represents a novel strategy with the potential to improve responses to ICB therapy in a broad range of solid tumors.ReferencesNagel D, Spranger S, Vincendeau M, Grau M, Raffegerst S, Kloo B, Hlahla D, Neuenschwander M, Peter von Kries J, Hadian K, Dörken B, Lenz P, Lenz G, Schendel DJ, Krappmann D. Pharmacologic inhibition of MALT1 protease by phenothiazines as a therapeutic approach for the treatment of aggressive ABC-DLBCL. Cancer Cell 2012 December 11;22(6):825–37.Di Pilato M, Kim EY, Cadilha BL, Prüßmann JN, Nasrallah MN, Seruggia D, Usmani SM, Misale S, Zappulli V, Carrizosa E, Mani V, Ligorio M, Warner RD, Medoff BD, Marangoni F, Villani AC, Mempel TR. Targeting the CBM complex causes Treg cells to prime tumours for immune checkpoint therapy. Nature 2019 June;570(7759):112–116.Lim SA, Wei J, Nguyen TM, Shi H, Su W, Palacios G, Dhungana Y, Chapman NM, Long L, Saravia J, Vogel P, Chi H. Lipid signalling enforces functional specialization of Treg cells in tumours. Nature 2021 March;591(7849):306–311.Zappasodi R, Serganova I, Cohen IJ, Maeda M, Shindo M, Senbabaoglu Y, Watson MJ, Leftin A, Maniyar R, Verma S, Lubin M, Ko M, Mane MM, Zhong H, Liu C, Ghosh A, Abu-Akeel M, Ackerstaff E, Koutcher JA, Ho PC, Delgoffe GM, Blasberg R, Wolchok JD, Merghoub T. CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours. Nature 2021 March;591(7851):652–658.Overacre-Delgoffe AE, Chikina M, Dadey RE, Yano H, Brunazzi EA, Shayan G, Horne W, Moskovitz JM, Kolls JK, Sander C, Shuai Y, Normolle DP, Kirkwood JM, Ferris RL, Delgoffe GM, Bruno TC, Workman CJ, Vignali DAA. Interferon-γ drives Treg fragility to promote anti-tumor immunity. Cell 2017 June 1;169(6):1130–1141.e11.Martin K, Junker U, Tritto E, Sutter E, Rubic-Schneider T, Morgan H, Niwa S, Li J, Schlapbach A, Walker D, Bigaud M, Beerli C, Littlewood-Evans A, Rudolph B, Laisney M, Ledieu D, Beltz K, Quancard J, Bornancin F, Zamurovic Ribrioux N, Calzascia T. Pharmacological inhibition of MALT1 protease leads to a progressive IPEX-Like pathology. Front Immunol 2020 April 30;11:745.

scholarly journals ROLE OF THE REGULATORY T CELLS IN PROGRESSION OF PROSTATE CANCER

2019 ◽  
Vol 21 (4) ◽  
pp. 587-594
Author(s):  
S. V. Popov ◽  
N. V. Sturov ◽  
N. V. Vorobyev ◽  
S. V. Khaidukov
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Regulatory T Cells ◽  
Prostate Gland ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Cancer Tissue ◽  
Clinical Prognosis ◽  
Treg Population ◽  
T Cell Subpopulations

The existing data on regulatory T cells (Tregs) in prostate cancer suggest that these cells may penetrate the prostate gland malignant tissue, suppressing antitumor immune response, thus promoting aggressive clinical course and low survival of the cancer patients. Evaluation of T cell subpopulations from the tumor microenvironment has shown that the number of CD4+Tregs is associated with inferior clinical prognosis. In particular, each additional CD4+Treg cell has been shown to cause a statistically significant increase in prostate cancer mortality by 12%, regardless of other clinical factors. There are several possible explanations for the increased infiltration of prostate cancer tissue with regulatory T cells. Firstly, malignant cells or tumor-associated macrophages are capable of secreting chemokine CCL22, which has an affinity for the CCR4 receptor expressed on Treg cells. Secondly, cytokines secreted by prostate tumors, such as TGF-β, may regulate the FoxP3 expression, thus expanding the Treg population. TGF-β, in turn, is a multifunctional cytokine that promotes survival and proliferation of transformed cells, including prostate epithelium, as evidenced by increased amounts in the patients with metastatic disease.

scholarly journals Regulatory T Cells Fail to Suppress Fast Homeostatic Proliferation In Vitro

Life ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 245
Author(s):  
Daniil Shevyrev ◽  
Valeriy Tereshchenko ◽  
Elena Blinova ◽  
Nadezda Knauer ◽  
Ekaterina Pashkina ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Autoimmune Diseases ◽  
Peripheral Blood ◽  
Treg Cells ◽  
Homeostatic Proliferation ◽  
Suppressive Activity ◽  
Healthy Donors

Homeostatic proliferation (HP) is a physiological process that reconstitutes the T cell pool after lymphopenia involving Interleukin-7 and 15 (IL-7 and IL-15), which are the key cytokines regulating the process. However, there is no evidence that these cytokines influence the function of regulatory T cells (Tregs). Since lymphopenia often accompanies autoimmune diseases, we decided to study the functional activity of Tregs stimulated by HP cytokines from patients with rheumatoid arthritis as compared with that of those from healthy donors. Since T cell receptor (TCR) signal strength determines the intensity of HP, we imitated slow HP using IL-7 or IL-15 and fast HP using a combination of IL-7 or IL-15 with anti-CD3 antibodies, cultivating Treg cells with peripheral blood mononuclear cells (PBMCs) at a 1:1 ratio. We used peripheral blood from 14 patients with rheumatoid arthritis and 18 healthy volunteers. We also used anti-CD3 and anti-CD3 + IL-2 stimulation as controls. The suppressive activity of Treg cells was evaluated in each case by the inhibition of the proliferation of CD4+ and CD8+ cells. The phenotype and proliferation of purified CD3+CD4+CD25+CD127lo cells were assessed by flow cytometry. The suppressive activity of the total pool of Tregs did not differ between the rheumatoid arthritis and healthy donors; however, it significantly decreased in conditions close to fast HP when the influence of HP cytokines was accompanied by anti-CD3 stimulation. The Treg proliferation caused by HP cytokines was lower in the rheumatoid arthritis (RA) patients than in the healthy individuals. The revealed decrease in Treg suppressive activity could impact the TCR landscape during lymphopenia and lead to the proliferation of potentially self-reactive T cell clones that are able to receive relatively strong TCR signals. This may be another explanation as to why lymphopenia is associated with the development of autoimmune diseases. The revealed decrease in Treg proliferation under IL-7 and IL-15 exposure can lead to a delay in Treg pool reconstitution in patients with rheumatoid arthritis in the case of lymphopenia.

scholarly journals Secretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mei Ding ◽  
Rajneesh Malhotra ◽  
Tomas Ottosson ◽  
Magnus Lundqvist ◽  
Aman Mebrahtu ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cell Function ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Secreted Proteins ◽  
External Stimulation ◽  
Marker Proteins ◽  
Positive Regulators ◽  
Conformational Model

AbstractRegulatory T cells (Tregs) are the key cells regulating peripheral autoreactive T lymphocytes. Tregs exert their function by suppressing effector T cells. Tregs have been shown to play essential roles in the control of a variety of physiological and pathological immune responses. However, Tregs are unstable and can lose the expression of FOXP3 and suppressive functions as a consequence of outer stimuli. Available literature suggests that secreted proteins regulate Treg functional states, such as differentiation, proliferation and suppressive function. Identification of secreted proteins that affect Treg cell function are highly interesting for both therapeutic and diagnostic purposes in either hyperactive or immunosuppressed populations. Here, we report a phenotypic screening of a human secretome library in human Treg cells utilising a high throughput flow cytometry technology. Screening a library of 575 secreted proteins allowed us to identify proteins stabilising or destabilising the Treg phenotype as suggested by changes in expression of Treg marker proteins FOXP3 and/or CTLA4. Four proteins including GDF-7, IL-10, PAP and IFNα-7 were identified as positive regulators that increased FOXP3 and/or CTLA4 expression. PAP is a phosphatase. A catalytic-dead version of the protein did not induce an increase in FOXP3 expression. Ten interferon proteins were identified as negative regulators that reduced the expression of both CTLA4 and FOXP3, without affecting cell viability. A transcriptomics analysis supported the differential effect on Tregs of IFNα-7 versus other IFNα proteins, indicating differences in JAK/STAT signaling. A conformational model experiment confirmed a tenfold reduction in IFNAR-mediated ISG transcription for IFNα-7 compared to IFNα-10. This further strengthened the theory of a shift in downstream messaging upon external stimulation. As a summary, we have identified four positive regulators of FOXP3 and/or CTLA4 expression. Further exploration of these Treg modulators and their method of action has the potential to aid the discovery of novel therapies for both autoimmune and infectious diseases as well as for cancer.

scholarly journals Trichostatin A Promotes the Generation and Suppressive Functions of Regulatory T Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Cristian Doñas ◽  
Macarena Fritz ◽  
Valeria Manríquez ◽  
Gabriela Tejón ◽  
María Rosa Bono ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Trichostatin A ◽  
Gene Promoter ◽  
Treg Cells ◽  
Specific Subset ◽  
Global Increase ◽  
And Function ◽  
H3 Acetylation

Regulatory T cells are a specific subset of lymphocytes that suppress immune responses and play a crucial role in the maintenance of self-tolerance. They can be generated in the thymus as well as in the periphery through differentiation of naïve CD4+T cells. The forkhead box P3 transcription factor (Foxp3) is a crucial molecule regulating the generation and function of Tregs. Here we show that thefoxp3gene promoter becomes hyperacetylated inin vitrodifferentiated Tregs compared to naïve CD4+T cells. We also show that the histone deacetylase inhibitor TSA stimulated thein vitrodifferentiation of naïve CD4+T cells into Tregs and that this induction was accompanied by a global increase in histone H3 acetylation. Importantly, we also demonstrated that Tregs generated in the presence of TSA have phenotypical and functional differences from the Tregs generated in the absence of TSA. Thus, TSA-generated Tregs showed increased suppressive activities, which could potentially be explained by a mechanism involving the ectonucleotidases CD39 and CD73. Our data show that TSA could potentially be used to enhance the differentiation and suppressive function of CD4+Foxp3+Treg cells.

scholarly journals CD38 Correlates with an Immunosuppressive Treg Phenotype in Lupus-Prone Mice

2021 ◽  
Vol 22 (21) ◽  
pp. 11977
Author(s):  
Jocelyn C. Pérez-Lara ◽  
Enrique Espinosa ◽  
Leopoldo Santos-Argumedo ◽  
Héctor Romero-Ramírez ◽  
Gabriela López-Herrera ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Activation ◽  
Lupus Erythematosus ◽  
Clinical Signs ◽  
Foxp3 Expression ◽  
Cell Receptor ◽  
Treg Cells ◽  
Transmembrane Glycoprotein ◽  
Ifn Γ

CD38 is a transmembrane glycoprotein expressed by T-cells. It has been reported that patients with systemic lupus erythematosus (SLE) showed increased CD38+CD25+ T-cells correlating with immune activation and clinical signs. Contrariwise, CD38 deficiency in murine models has shown enhanced autoimmunity development. Recent studies have suggested that CD38+ regulatory T-cells are more suppressive than CD38− regulatory T-cells. Thus, we have suggested that CD38 overexpression in SLE patients could play a role in regulating immune activation cells instead of enhancing it. This study found a correlation between CD38 with FoxP3 expression and immunosuppressive molecules (CD69, IL-10, CTLA-4, and PD-1) in T-cells from lupus-prone mice (B6.MRL-Faslpr/J). Additionally, B6.MRL-Faslpr/J mice showed a decreased proportion of CD38+ Treg cells regarding wild-type mice (WT). Furthermore, Regulatory T-Cells (Treg cells) from CD38-/- mice showed impairment in expressing immunosuppressive molecules and proliferation after stimulation through the T-cell receptor (TCR). Finally, we demonstrated an increased ratio of IFN-γ/IL-10 secretion in CD38-/- splenocytes stimulated with anti-CD3 compared with the WT. Altogether, our data suggest that CD38 represents an element in maintaining activated and proliferative Treg cells. Consequently, CD38 could have a crucial role in immune tolerance, preventing SLE development through Treg cells.

scholarly journals Cooperation between Cancer Cells and Regulatory T Cells to Promote Immune-escape through Integrin αvβ8-Mediated TGF-β Activation

2021 ◽  
Author(s):  
Alexandra Laine ◽  
Ossama Labiad ◽  
Hector Hernandez-Vargas ◽  
Sebastien This ◽  
Amélien Sanlaville ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Regulatory T Cells ◽  
Cancer Cells ◽  
Immune Escape ◽  
Antibody Treatment ◽  
Inactive Form ◽  
Treg Population ◽  
Cytotoxic Function ◽  
Made In

Abstract Among the strategies allowing cancer cells to escape the immune system, the presence of TGF-b in the tumor micro-environment is one of the most potent. However, TGF-b is secreted in an inactive form and mechanisms responsible for its activation within the tumor remain unknown. Here, we demonstrate that regulatory T cells (Tregs) compose the main cells expressing the b8 chain of avb8 integrin (Itgb8) in the tumors and that the Itgb8pos Treg population activates TGF-b produced by the cancer cells and stored in the tumor micro-environment. Itgb8 ablation in Tregs impaired TGF-b signaling in T lymphocytes present in the tumor but not in the tumor draining lymph nodes. The cytotoxic function of CD8pos T lymphocytes infiltrating the tumors was subsequently exacerbated leading to an efficient control of the tumor growth. Similar observations were made in patient tumors after anti-Itgb8 antibody treatment. Thus, this study reveals that Tregs work in concert with cancer cells to produce bioactive-TGF-b and create a powerful-immunosuppressive micro-environment.

scholarly journals The Complex Role of Regulatory T Cells in Immunity and Aging

2021 ◽  
Vol 11 ◽  
Author(s):  
Lourdes Rocamora-Reverte ◽  
Franz Leonard Melzer ◽  
Reinhard Würzner ◽  
Birgit Weinberger
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Immune Cells ◽  
Treg Cells ◽  
T Cell Subsets ◽  
Γδt Cells ◽  
Cell Functions ◽  
Age Related ◽  
Self Antigens

The immune system is a tightly regulated network which allows the development of defense mechanisms against foreign antigens and tolerance toward self-antigens. Regulatory T cells (Treg) contribute to immune homeostasis by maintaining unresponsiveness to self-antigens and suppressing exaggerated immune responses. Dysregulation of any of these processes can lead to serious consequences. Classically, Treg cell functions have been described in CD4+ T cells, but other immune cells also harbour the capacity to modulate immune responses. Regulatory functions have been described for different CD8+ T cell subsets, as well as other T cells such as γδT cells or NKT cells. In this review we describe the diverse populations of Treg cells and their role in different scenarios. Special attention is paid to the aging process, which is characterized by an altered composition of immune cells. Treg cells can contribute to the development of various age-related diseases but they are poorly characterized in aged individuals. The huge diversity of cells that display immune modulatory functions and the lack of universal markers to identify Treg make the expanding field of Treg research complex and challenging. There are still many open questions that need to be answered to solve the enigma of regulatory T cells.

Abstract T MP18: In Vivo Expansion of Regulatory T cells with Interleukin-2/Interleukin-2-antibody Complex Protects against Transient Ischemic Stroke

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Haiyue Zhang ◽  
Peiying Li ◽  
Yanqin Gao ◽  
Jun Chen ◽  
Xiaoming Hu
Keyword(s):  
T Cells ◽  
Ischemic Stroke ◽  
Brain Injury ◽  
Regulatory T Cells ◽  
Interleukin 2 ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Treg Population ◽  
Antibody Complex

Background and Purpose: Our previous work documents the transfer of regulatory T cells (Tregs) in rodent models of ischemic stroke protects acute ischemic brain injury by regulating poststroke inflammatory response and thereby ameliorating BBB disruption. However, the low number of Tregs restricts the clinical feasibility of Treg transfer. Recently, in vivo expansion of Tregs with IL-2/IL-2-antibody complex (IL-2/IL-2Ab) was validated protective in autoimmune diseases model,renal ischemia reperfusion model and atherosclerosis. Here we investigate the beneficial effect of IL-2/IL-2Ab on ischemic stroke and decipher the underlying mechanisms. Methods: IL-2/IL-2Ab or isotype IgG was ip injected into C57/BL6 mice for 3 consecutive days. The mice are then subjected to 60-minute middle cerebral artery occlusion (MCAO) or sham operation. Brain infarction, inflammation and neurological performance was assessed up to 7 days after reperfusion. Results: Flow cytometry analysis reveals a marked increase of CD4+CD25+Foxp3+ Tregs in the blood, lymph nodes and spleens collected from IL-2/IL-2Ab-treated mice as compared to those from isotype-treated controls. Such Treg elevation could be observed since 3 days after IL-2/IL-2Ab injection and lasts until 7 days after MCAO. Immunochemistry staining confirms the increased number of Foxp3+ cells in the spleen at 3 days after MCAO in IL-2/IL-2Ab-treated mice. IL-2/IL-2Ab promotes function recovery up to 7 days after stroke, as revealed by significantly improved performance in corner test (n=6-9, ***p<0.001), rotarod test (n=8, **p<0.01), cylinder test (n=8, **p<0.01) and adhesive removal test (n=3, *p<0.05). Quantification of TTC staining and microtubule-associated protein (MAP2) staining shows reductions in brain infarct volume at 3 days (n=5-9,*p<0.05) and 7 days (n=7-9,*p<0.01), respectively, after MCAO. Meanwhile, we observed reduced infiltration of peripheral immune cells (CD3+ T cells, MPO+ neutrophils and F4/80+ macrophages) into the ischemic brain. Conclusions: Our finding suggests that IL-2/IL-2Ab treatment is a novel and clinical feasible immune therapy to expand Treg population in vivo, reduce post-stroke inflammatory responses and protect against ischemic brain injury.

scholarly journals Regulatory T Cells, a Potent Immunoregulatory Target for CAM Researchers: The Ultimate Antagonist (I)

2006 ◽  
Vol 3 (1) ◽  
pp. 25-30 ◽  
Author(s):  
Aristo Vojdani ◽  
Jonathan Erde
Keyword(s):  
T Cells ◽  
Immune System ◽  
Regulatory T Cells ◽  
Host Defense ◽  
Western Medicine ◽  
Treg Cells ◽  
Active Suppression ◽  
Beneficial Effects ◽  
The Past ◽  
Powerful Means

Over the past decade, great interest has been given to regulatory T (Treg) cells. A vast body of evidence has shown the existence and highlighted the importance of Treg cells in the active suppression of immune system responses. This form of immunoregulation is the dominant means utilized by the immune system to reach a harmony between reciprocal response processes in order to ensure adequate host defense with minimal host detriment. Therapeutically targeting Treg cells is a direct and powerful means to manipulate the immune system to achieve beneficial effects on various disease pathologies, including allergy, autoimmunity and cancer, as well as the facilitation of organ transplantation. This powerful target for immunoregulation is of much concern to practitioners and researchers of complementary and alternative medicine because it allows a great deal of control and certainty in dealing with the prevalence of debilitating immune system-related disorders for which there has been little remedy outside of Western Medicine.

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