scholarly journals Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation.

1996 ◽  
Vol 184 (2) ◽  
pp. 387-396 ◽  
Author(s):  
M Asano ◽  
M Toda ◽  
N Sakaguchi ◽  
S Sakaguchi
Keyword(s):  
T Cells ◽  
Autoimmune Diseases ◽  
Spleen Cell ◽  
Interleukin 2 ◽  
Cell Suspensions ◽  
Cell Subpopulation ◽  
Adult Mice ◽  
Self Tolerance ◽  
Organ Specific ◽  
Cytokine Formation

Neonatal thymectomy (NTx), especially around day 3 after birth, causes various organ-specific autoimmune diseases in mice. This report shows that: (a) T cells expressing the interleukin 2 receptor alpha chains (CD25) ontogenically begin to appear in the normal periphery immediately after day 3, rapidly increasing within 2 wk to nearly adult levels (approximately 10% of CD3+ cells, especially of CD4+ cells); (b) NTx on day 3 eliminates CD25+ T cells from the periphery for several days; inoculation immediately after NTx of CD25+ splenic T cells from syngeneic non-Tx adult mice prevents autoimmune development, whereas inoculation of CD25- T cells even at a larger dose does not; and furthermore, (c) similar autoimmune diseases can be produced in adult athymic nu/nu mice by inoculating either spleen cell suspensions from 3-d-old euthymic nu/+ mice or CD25+ cell-depleted spleen cell suspensions from older, even 1-yr-old, nu/+ mice. The CD25- populations from neonates or adults are also similar in the profile of cytokine formation. These results, taken together, indicate that one aspect of peripheral self-tolerance is maintained by CD25+ T cells that sustain potentially pathogenic self-reactive T cells in a CD25- dormant state; the thymic production of the former is developmentally programmed to begin on day 3 after birth in mice. Thus, NTx on day 3 can, at least transiently, eliminate/reduce the autoimmune-preventive CD25+ T cells, thereby leading to activation of the self-reactive T cells that have been produced before NTx.

scholarly journals Thymus and autoimmunity. Transplantation of the thymus from cyclosporin A-treated mice causes organ-specific autoimmune disease in athymic nude mice.

1988 ◽  
Vol 167 (4) ◽  
pp. 1479-1485 ◽  
Author(s):  
S Sakaguchi ◽  
N Sakaguchi
Keyword(s):  
T Cells ◽  
Autoimmune Disease ◽  
Autoimmune Diseases ◽  
Cyclosporin A ◽  
Spleen Cell ◽  
Nude Mice ◽  
Cell Suspensions ◽  
Suppressor T Cells ◽  
Athymic Nude Mice ◽  
Organ Specific

Organ-specific autoimmune diseases such as gastritis, oophoritis, thyroiditis, or insulitis developed in athymic nu/nu mice after engraftment of the thymus from euthymic nu/+ mice treated with cyclosporin A (CsA), a potent immuno-suppressant. The development of autoimmune disease in the nu/nu mice was prevented by inoculation of thymocyte suspensions prepared from normal nu/+ mice, but not by thymocyte suspensions from CsA-treated nu/+ mice. Cotransplantation of normal nu/+ mouse thymus with CsA-treated thymus also suppressed the development of autoimmune disease. Inoculation of spleen cell suspensions prepared from normal adult nu/+ mice prevented autoimmune disease, but inoculation of those from newborn nu/+ mice did not. Thus, CsA appears to interfere selectively with the thymic production of certain suppressor T cells controlling self-reactive (autoimmune) T cells, allowing the latter to expand and cause autoimmune disease.

scholarly journals THU0051 LOW-DOSE INTERLEUKIN-2 SELECTIVELY EXPAND AND ACTIVATE REGULATORY T CELLS ACROSS 13 AUTOIMMUNE DISEASES.

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 237.1-238
Author(s):  
M. Rosenzwajg ◽  
R. Lorenzon ◽  
P. Cacoub ◽  
F. Pitoiset ◽  
S. Aractingi ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Autoimmune Diseases ◽  
Inflammatory Disease ◽  
Low Dose ◽  
Therapeutic Potential ◽  
Interleukin 2 ◽  
Clinical Effects ◽  
Research Support ◽  
Open Label

Background:Regulatory T cells (Tregs) prevent autoimmunity and control inflammation. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential for any autoimmune or inflammatory disease (AIID). We performed a disease-finding “basket trial” (TRANSREGNCT01988506) in patients affected by one of 11 different AIID and reported the outcome of the first 46 patients (Rosenzwajg et al, ARD 2019).Objectives:Here we analyzed and discussed results from deep immunophenotyping, of 78 patients, to comprehensively study the effect of ld-IL2 on the immune system of patients affected by various AIIDMethods:We performed a prospective, open label, phase I-IIa study in 78 patients with a mild to moderate form of one of 13 selected AIID. All patients received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Deep immunophenotyping was performed before and after 5 days of ld-IL2.Results:ld-IL2 significantly expands both memory Tregs as well as naïve Tregs, including recent thymic emigrant Tregs. It also activates Tregs as demonstrated by the significantly increased expression of HLA-DR, CD39, CD73, GITR, CTLA-4. Similar results were observed across the different AIID.Conclusion:ld-IL2 “universally” improves Treg fitness across 13 autoimmune and inflammatory disease.References:[1]Rosenzwajg M#, Lorenzon R#, Cacoub P, Pham HP, Pitoiset F, El Soufi K, RIbet C, Bernard C, Aractingi S, Banneville B, Beaugerie L, Berenbaum F, Champey J, Chazouilleres O, Corpechot C, Fautrel B, Mekinian A, Regnier E, Saadoun D, Salem JE, Sellam J, Seksik P, Daguenel-Nguyen A, Doppler V, Mariau J, Vicaut E, Klatzmann D. Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial. Ann Rheum Dis. 2019 Feb;78(2):209-217. doi: 10.1136/annrheumdis-2018-214229. Epub 2018 Nov 24.Disclosure of Interests:Michelle Rosenzwajg: None declared, Roberta Lorenzon: None declared, Patrice cacoub: None declared, Fabien Pitoiset: None declared, Selim Aractingi: None declared, Beatrice Banneville Speakers bureau: Lilly, Novartis, Laurent Beaugerie: None declared, Francis Berenbaum Grant/research support from: TRB Chemedica (through institution), MSD (through institution), Pfizer (through institution), Consultant of: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Bone Therapeutics, Regulaxis, Peptinov, 4P Pharma, Paid instructor for: Sandoz, Speakers bureau: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Sandoz, Julien Champey: None declared, Olivier Chazouilleres: None declared, Christophe Corpechot: None declared, Bruno Fautrel Grant/research support from: AbbVie, Lilly, MSD, Pfizer, Consultant of: AbbVie, Biogen, BMS, Boehringer Ingelheim, Celgene, Lilly, Janssen, Medac MSD France, Nordic Pharma, Novartis, Pfizer, Roche, Sanofi Aventis, SOBI and UCB, Arsene Mekinian: None declared, Elodie Regnier: None declared, david Saadoun: None declared, Joe-Elie Salem: None declared, Jérémie SELLAM: None declared, Philippe Seksik: None declared, David Klatzmann Consultant of: ILTOO Pharma

scholarly journals Defective Suppressor Function of Human CD4+ CD25+ Regulatory T Cells in Autoimmune Polyglandular Syndrome Type II

2004 ◽  
Vol 199 (9) ◽  
pp. 1285-1291 ◽  
Author(s):  
Martin A. Kriegel ◽  
Tobias Lohmann ◽  
Christoph Gabler ◽  
Norbert Blank ◽  
Joachim R. Kalden ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Autoimmune Diseases ◽  
Type I ◽  
Type Ii ◽  
Central Tolerance ◽  
Autoimmune Polyglandular Syndrome ◽  
Healthy Donors ◽  
Organ Specific ◽  
Autoimmune Polyglandular Syndrome Type

In autoimmune polyglandular syndromes (APS), several organ-specific autoimmune diseases are clustered. Although APS type I is caused by loss of central tolerance, the etiology of APS type II (APS-II) is currently unknown. However, in several murine models, depletion of CD4+ CD25+ regulatory T cells (Tregs) causes a syndrome resembling human APS-II with multiple endocrinopathies. Therefore, we hypothesized that loss of active suppression in the periphery could be a hallmark of this syndrome. Tregs from peripheral blood of APS-II, control patients with single autoimmune endocrinopathies, and normal healthy donors showed no differences in quantity (except for patients with isolated autoimmune diseases), in functionally important surface markers, or in apoptosis induced by growth factor withdrawal. Strikingly, APS-II Tregs were defective in their suppressive capacity. The defect was persistent and not due to responder cell resistance. These data provide novel insights into the pathogenesis of APS-II and possibly human autoimmunity in general.

Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases

1995 ◽  
Vol 16 (1) ◽  
pp. 34-38 ◽  
Author(s):  
Roland S. Liblau ◽  
Steven M. Singer ◽  
Hugh O. McDevitt
Keyword(s):  
T Cells ◽  
Autoimmune Diseases ◽  
Cd4 T Cells ◽  
Organ Specific ◽  
Th1 And Th2

scholarly journals Thymus and autoimmunity: capacity of the normal thymus to produce pathogenic self-reactive T cells and conditions required for their induction of autoimmune disease.

1990 ◽  
Vol 172 (2) ◽  
pp. 537-545 ◽  
Author(s):  
S Sakaguchi ◽  
N Sakaguchi
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Autoimmune Disease ◽  
Autoimmune Diseases ◽  
Rheumatoid Factors ◽  
Systemic Autoimmune Diseases ◽  
Organ Specific ◽  
Gastric Parietal Cells

BALB/c athymic nu/nu mice spontaneously developed organ-specific (gastritis, thyroiditis, oophoritis, or orchitis) and systemic (arteritis, glomerulonephritis, and polyarthritis) autoimmune diseases when transplanted with neonatal BALB/c thymuses. Transplantation of thymuses from adult BALB/c mice was far less effective in inducing histologically evident organ-specific autoimmune disease in nu/nu mice. Autoimmune disease developed, however, when adult thymuses were irradiated at a T cell-depleting dose before transplantation. Engrafting newborn thymuses into BALB/c mice T cell depleted by thymectomy, irradiation, and bone marrow transplantation produced similar organ-specific autoimmune disease as well, but thymus engrafting into T cell-nondepleted BALB/c mice (i.e., mice thymectomized as adults, but not irradiated) did not, despite the fact that transplanted thymuses grew well in both groups of mice. The mice with organ-specific autoimmune disease produced autoantibodies specific for the respective organ components, such as gastric parietal cells, thyroglobulins, oocytes, or sperm. The thymus-transplanted nu/nu mice also had hypergammaglobulinemia and developed anti-DNA autoantibodies, rheumatoid factors, and immune complexes in the circulation. These results indicate that: (a) the thymus of a murine strain that does not develop spontaneous autoimmune disease can produce pathogenic self-reactive T cells that mediate organ-specific and/or systemic autoimmune diseases; and (b) such self-reactive T cells, especially those mediating organ-specific autoimmune disease, spontaneously expand and cause autoimmune disease when released to the T cell-deficient or -eliminated periphery.

scholarly journals STAT3 deficiency in B cells exacerbates uveitis by promoting expansion of pathogenic lymphocytes and suppressing regulatory B cells (Bregs) and Tregs

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Favour O. Oladipupo ◽  
Cheng-Rong Yu ◽  
Ezekiel Olumuyide ◽  
Yingyos Jittaysothorn ◽  
Jin Kyeong Choi ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Autoimmune Diseases ◽  
B Lymphocyte ◽  
Kinase Inhibitors ◽  
Autoimmune Encephalitis ◽  
Cyclin Dependent Kinase ◽  
Organ Specific ◽  
Enhanced Expression ◽  
Experimental Autoimmune

Abstract STAT3 transcription factor induces differentiation of naïve T cells into Th17 cells and loss of STAT3 in T cell prevents development of CNS autoimmune diseases. However, function of STAT3 in the B lymphocyte subset is not well understood. In this study, we have generated mice lacking STAT3 in CD19+ B cells (CD19-STAT3KO) and investigated intrinsic and extrinsic functions of STAT3 in B cells and its potential role in resistance or pathogenesis of organ-specific autoimmune diseases. We show that STAT3 regulates metabolic mechanisms in B cells with implications for bioenergetic and metabolic pathways that control cellular homeostasis in B cells. Thus, loss of STAT3 in CD19-STAT3KO cells perturbed growth and apoptosis by inducing rapid entry of B cells into the S-phase of the cell cycle, decreasing expression of cyclin-dependent kinase inhibitors and upregulating pro-apoptotic proteins. We further show that the CD19-STAT3KO mice develop severe experimental autoimmune uveitis (EAU), an animal model of human uveitis. Exacerbated uveitis in CD19-STAT3KO mice derived in part from enhanced expression of costimulatory molecules on B cells, marked increase of Th17 responses and increased recruitment of granulocytes into the neuroretina. The enhanced autoimmunity upon deletion of STAT3 in B cells is also recapitulated in experimental autoimmune encephalitis, a mouse model of multiple sclerosis and thus support our conclusion that STAT3 deletion in B cells enhanced inflammation and the effects observed are not model specific. Our data further indicate that STAT3 pathway modulates interactions between B and T cells during EAU resulting in alteration of lymphocyte repertoire by increasing levels of autoreactive pathogenic T cells while suppressing development and/or expansion of immune-suppressive lymphocytes (Bregs and Tregs). Taken together, STAT3 exerts diametrically opposite effects in lymphocytes, with loss of STAT3 in B cells exacerbating uveitis whereas Stat3 deletion in T cells confers protection.

Low-dose Interleukin-2 in the Treatment of Autoimmune Disease

2014 ◽  
Vol 10 (02) ◽  
pp. 157 ◽  
Author(s):  
John Koreth ◽  
Jerome Ritz ◽  
George C Tsokos ◽  
Alberto Pugliese ◽  
Thomas R Malek ◽  
...  
Keyword(s):  
T Cells ◽  
Autoimmune Diseases ◽  
Lupus Erythematosus ◽  
Low Dose ◽  
Cell Function ◽  
Interleukin 2 ◽  
The Us ◽  
High Doses ◽  
And Function ◽  
Preclinical And Clinical Studies

CD4+ regulatory T cells (Tregs) act to maintain peripheral immune tolerance. Decreased numbers or defective function of Tregs has been implicated in the pathogenesis of various autoimmune diseases. Interleukin-2 (IL-2) at high doses is approved by the US Food and Drug Administration (FDA) as an immune stimulant to induce anti-tumor cytotoxicity. However, at physiologic doses, IL-2 is necessary for the expansion and function of Tregs. Treatment with low-dose IL-2 can selectively enhance Treg function while avoiding the activation of effector T cells and ameliorate immune inflammation. Administration of low doses of IL-2 to patients suffering from chronic graft versus host disease (cGvHD) or chronic hepatitis C-mediated vasculitis resulted in significant clinical benefit, which was linked to improved Treg cell function. Preclinical studies suggest that low-dose IL-2 may offer benefit in other autoimmune diseases including systemic lupus erythematosus and type 1 diabetes. Ongoing preclinical and clinical studies indicate a wider potential role for low-dose IL-2 based Treg therapeutics in human autoimmune diseases.

Refractory juvenile idiopathic arthritis: using autologous stem cell transplantation as a treatment strategy

2006 ◽  
Vol 8 (26) ◽  
pp. 1-11 ◽  
Author(s):  
Nico M. Wulffraat ◽  
Ismé M. de Kleer ◽  
Berent Prakken
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Juvenile Idiopathic Arthritis ◽  
Stem Cell Transplantation ◽  
Autoimmune Diseases ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Allogeneic Bone ◽  
Self Tolerance ◽  
A Cell

Cellular immune therapy for severe autoimmune diseases can now be considered when such patients are refractory to conventional treatment. The use of autologous stem cell transplantation (ASCT) to treat human autoimmune diseases has been initiated following promising results in a variety of animal models. Anecdotal observations have been made of autoimmune disease remission in patients who have undergone allogeneic bone marrow transplantation as a result of coincidental haematological malignancies. The possibility of inducing immunological self-tolerance by ASCT is particularly attractive as a means for treating juvenile idiopathic arthritis (JIA). In this disease, ASCT restores self-tolerance both through a cell-intrinsic mechanism, involving the reprogramming of autoreactive T cells, and through a cell-extrinsic mechanism, involving a renewal of the immune balance between CD4+CD25+ regulatory T cells and other T cells. This review describes the clinical results of ASCT performed for this disease and the possible underlying immunological mechanisms.

scholarly journals Growth of epithelial cells in the thymic medulla is under the control of mature T cells.

1992 ◽  
Vol 176 (2) ◽  
pp. 611-616 ◽  
Author(s):  
C D Surh ◽  
B Ernst ◽  
J Sprent
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epithelial Cells ◽  
Tolerance Induction ◽  
Scid Mice ◽  
Adult Mice ◽  
Large Numbers ◽  
Self Tolerance ◽  
Thymic Medulla ◽  
Cellular Components

Epithelial cells in the thymic medulla are conspicuous in normal adult mice, but sparse in the early fetal thymus and the thymus of adult T cell-deficient SCID mice. To examine whether growth of medullary epithelial cells (MEC) depends upon local contact with mature T cells, we used the finding that the SCID thymus is unusually permeable to mature T cells entering from the bloodstream. When SCID mice received multiple injections of mature lymph node T cells from birth, the thymus accumulated large numbers of mature TCR+ T cells of resting phenotype, but contained virtually no immature (CD4+8+) cells. The injected T cells localized in the medullary region of the thymus and led to marked regeneration of MEC. These and other data suggest that the growth of MEC is under the control of mature T cells. Placing MEC under T cell control might be a device for regulating the size and integrity of the medulla, especially during the phase of rapid thymic growth. Maintaining the cellular components of the medulla in proper balance could be critical for ensuring efficient self tolerance induction.

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