scholarly journals Homeostatic T Cell Proliferation after Islet Transplantation

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Paolo Monti ◽  
Lorenzo Piemonti
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Islet Transplantation ◽  
T Cell Proliferation ◽  
Pancreatic Islet Transplantation ◽  
Therapeutic Approaches ◽  
Cell Responses ◽  
New Therapeutic Approaches ◽  
Alloreactive T Cell

Pancreatic islet transplantation in patients with type 1 diabetes mellitus is performed under immunosuppression to avoid alloreactive T cell responses and to control the reactivation of autoreactive memory T cells. However, lymphopenia associated with immunosuppression and T cell depletion can induce a paradoxical expansion of lymphocyte subsets under the influence of homeostatic proliferation. Homeostatic T cell proliferation is mainly driven by the IL-7/IL-7 receptor axis, a molecular pathway which is not affected by standard immune-suppressive drugs and, consequently, represents a novel potential target for immuno-modulatory strategies. In this review, we will discuss how homeostatic T cell proliferation can support autoimmunity recurrence after islet transplantation and how it can be targeted by new therapeutic approaches.

In Vitro Methotrexate: A Practical Approach to Selective Allodepletion.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5181-5181
Author(s):  
Atul Sathe ◽  
Sterling Ortega ◽  
Dorothy Mundy ◽  
Robert H. Collins ◽  
Nitin J. Karandikar
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cell ◽  
Third Party ◽  
T Cell Proliferation ◽  
Cell Responses ◽  
Viral Responses ◽  
Alloreactive T Cell

Abstract Graft-versus-Host Disease (GvHD) remains a major cause of transplant-related morbidity and mortality in recipients of allogeneic hematopoietic stem cell transplantation (AHSCT). Selective depletion of alloreactive T-cells may alleviate GvHD, while still maintaining other advantages conferred by donor T-cells, such as graft survival, antiviral immunity and graft-versus-leukemia effect. While several strategies for in vitro allodepletion have been proposed, their transition from pre-clinical studies to clinical use is sometimes hindered due to choice of reagent or technique. In this study, we evaluated the potential use of methotrexate (MTX), an FDA-approved drug known to inhibit T-cell proliferation, as an agent for specific in vitro allodepletion. Using a sensitive, flow cytometry-based proliferation assay, we first evaluated the effect of MTX on CD4+ and CD8+ T-cell proliferation in an HLA-mismatched one-way MLR. Addition of MTX resulted in significant inhibition of both CD4+ and CD8+ T-cell proliferation in MLR as well as superantigen-stimulated control reactions (n=14; p<0.001). We next evaluated whether this exposure to MTX resulted in selective allodepletion. Thus, live cells isolated from MTX-exposed MLR cultures were re-exposed to multiple stimuli, including the same allostimulus, a third-party allostimulus, cytomegalovirus (CMV) antigen and the superantigen SEB. We observed that CD4+ and CD8+ T-cell responses to same allo-stimulus were significantly abrogated, whereas T-cell responses to third-party stimuli, CMV and SEB were all preserved (n=12; p<0.01). These results provide strong pre-clinical evidence that in vitro treatment with MTX, a practical FDA-approved agent, results in specific allodepletion and may be used as an effective approach for preventing or minimizing GvHD. Inhibition of alloreactive T-cell proliferation by MTX Inhibition of alloreactive T-cell proliferation by MTX Loss of response to same allostimulus with preservation of “third party” and anti-viral responses in MTX-treated T-cells Loss of response to same allostimulus with preservation of “third party” and anti-viral responses in MTX-treated T-cells

scholarly journals T-cell mediated autoimmunity to the insulinoma-associated protein 2 islet tyrosine phosphatase in type 1 diabetes mellitus

1999 ◽  
pp. 272-278 ◽  
Author(s):  
F Dotta ◽  
S Dionisi ◽  
V Viglietta ◽  
C Tiberti ◽  
MC Matteoli ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Type 1 Diabetes ◽  
T Cell ◽  
T Lymphocyte ◽  
Tyrosine Phosphatase ◽  
T Cell Response ◽  
T Cell Proliferation ◽  
Diabetic Patients ◽  
Hla Dr

The target molecules of the T-cell response in type 1 diabetes, despite their pathogenic importance, remain largely uncharacterized, especially in humans. Interestingly, molecules such as insulin and glutamic acid decarboxylase (GAD) have been shown to be a target not only of autoantibodies, but also of autoreactive T-lymphocytes both in man and in the non-obese diabetic (NOD) mouse. In the present study we aimed to determine the existence of a specific T-cell response towards the insulinoma-associated protein 2 (IA-2) islet tyrosine phosphatase, a recently identified autoantigen which is the target of autoantibodies strongly associated with diabetes development. Human recombinant IA-2 produced in Escherichia coli, was tested for its reactivity with peripheral blood lymphocytes obtained from 16 newly diagnosed type 1 diabetic patients and from 25 normal controls, 15 of whom were HLA-DR-matched. A T-cell proliferation assay was performed in triplicate employing freshly isolated cells in the absence or in the presence of the antigen to be tested (at two different concentrations: 2 microg/ml and 10 microg/ml). A specific T-cell proliferation (defined as a stimulation index (S.I.) >/=3) was observed against IA-2 used at a concentration of 10 microg/ml (but not of 2 microg/ml) in 8/16 diabetic patients, in 1/15 HLA-DR-matched control subjects (P<0.01 by Fisher exact test) and in 0/10 of the remaining normal individuals. A statistically significant difference (P<0.003 by Mann-Whitney U test) was also observed in S.I. values between patients (3.1+/-1.4) and HLA-DR-matched controls (1.7+/-0.54) employing IA-2 at a concentration of 10 microg/ml. However, when IA-2 was used at a concentration of 2 microg/ml, the difference in S. I. between patients (1.65+/-0.8) and controls (1.0+/-0.3) did not reach statistical significance. In conclusion, these data show the presence of a specific, dose-dependent T-lymphocyte response against the IA-2 islet tyrosine phosphatase at the onset of type 1 diabetes. Consequently, this molecule appears to be a target not only at the B-lymphocyte but also at the T-lymphocyte level, reinforcing the potential pathogenic role of this autoantigen in the islet destructive process.

Nitric oxide-producing CD11b+Ly-6G(Gr-1)+CD31(ER-MP12)+cells in the spleen of cyclophosphamide–treated mice: implications for T-cell responses in immunosuppressed mice

Blood ◽  
2000 ◽  
Vol 95 (1) ◽  
pp. 212-220 ◽  
Author(s):  
Iñigo Angulo ◽  
Federico Gómez de las Heras ◽  
José F. Garcı́a-Bustos ◽  
Domingo Gargallo ◽  
M. Angeles Muñoz-Fernández ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cell Proliferation ◽  
T Cell ◽  
T Cell Responses ◽  
T Cell Proliferation ◽  
Intensive Chemotherapy ◽  
Suppressive Activity ◽  
Cell Responses ◽  
Nos Inhibitors ◽  
Ifn Γ

Abstract During recovery from intensive chemotherapy with cyclophosphamide (CTX), mice suffer a severe but transitory impairment in spleen cell proliferation to T-cell mitogens (Con A or anti-CD3 plus IL-2). Although CTX treatment reduced spleen T-cell cellularity, this cannot fully account for T-cell unresponsiveness. The results showed that CTX induces the colonization of spleen by an immature myeloid CD11b+Ly-6G+CD31+ population. Its presence closely correlated with the maximum inhibition of T-cell proliferation. Moreover, this suppressive activity was dependent on nitric oxide (NO) production in cultures since (1) higher amounts of nitric oxide and inducible nitric oxide synthase (iNOS) mRNA were produced in CTX spleen cells (CTX-SC) than in control splenocyte cultures and (2) NOS inhibitors greatly improved the proliferation of T lymphocytes. Nitric oxide production and suppressive activity were also dependent on endogenous interferon-γ (IFN-γ) production since anti–IFN-γ abrogated both effects. Finally, iNOS protein expression was restricted to a heterogeneous population of CD31+cells in which CD11b+Ly-6G+ cells were required to suppress T-cell proliferation. These results indicated that CTX might also cause immunosuppression by a mechanism involving the presence of immature myeloid cells with suppressor activity. This may have implications in clinical praxis since inappropriate immunotherapies in patients treated with intensive chemotherapy could lead to deleterious T-cell responses. (Blood. 2000;95:212-220)

scholarly journals Species specificity and augmentation of responses to class II major histocompatibility complex molecules in human CD4 transgenic mice.

1992 ◽  
Vol 175 (6) ◽  
pp. 1707-1715 ◽  
Author(s):  
E Barzaga-Gilbert ◽  
D Grass ◽  
S K Lawrance ◽  
P A Peterson ◽  
E Lacy ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Class Ii ◽  
T Cell Proliferation ◽  
Human Class ◽  
Cell Responses ◽  
Histocompatibility Complex ◽  
Species Specific

Murine T cell responses to human class II major histocompatibility complex (MHC) molecules were shown to be a minimum of 20-70-fold lower than responses to allogeneic molecules. Transgenic mice expressing slightly below normal (75-95%) or very high (250-380%) cell surface levels of human CD4 were utilized to determine whether this was due to a species-specific interaction between murine CD4 and class II molecules. Human CD4 was shown to function in signal transduction events in murine T cells based on the ability of anti-human CD4 antibody to synergize with suboptimal doses of anti-murine CD3 antibody in stimulating T cell proliferation. In mice expressing lower levels of human CD4, T cell responses to human class II molecules were enhanced up to threefold, whereas allogeneic responses were unaltered. In mice expressing high levels of human CD4, responses to human class II molecules were enhanced at least 10-fold, whereas allogeneic responses were between one and three times the level of normal responses. The relatively greater enhancement of the response to human class II molecules in both lines argues for a preferential interaction between human CD4 and human class II molecules. In mice expressing lower levels of human CD4, responses to human class II molecules were blocked by antibodies to CD4 of either species, indicating participation by both molecules. In mice expressing high levels of human CD4, responses to both human and murine class II molecules were almost completely blocked with anti-human CD4 antibody, whereas anti-murine CD4 antibody had no effect. However, anti-murine CD4 continued to synergize with anti-CD3 in stimulating T cell proliferation in these mice. Thus, overexpression of human CD4 selectively impaired the ability of murine CD4 to assist in the process of antigen recognition. The ability of human CD4 to support a strong allogeneic response under these conditions indicates that this molecule can interact with murine class II molecules to a significant extent. Despite the fact that human CD4 appeared to be the only functional coreceptor in these mice, responses to human class II molecules were still much lower than those to murine class II alloantigens. This indicates that species-specific interactions between class II molecules and CD4 expressed on peripheral T cells are not sufficient to account for the low xenogeneic response and that intrinsic differences in T cell receptor structures or the need for species specificity in the interaction between CD4 and class II molecules during positive selection are also important.

T Cells Response and Autoantibodies to Human Heat Shock Proteins in Aplastic Anemia Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2403-2403
Author(s):  
Yunfeng Cheng ◽  
Yong Tang ◽  
Neal S. Young
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Heat Shock ◽  
Heat Shock Proteins ◽  
Aplastic Anemia ◽  
T Cell Proliferation ◽  
Control Group ◽  
Cell Responses ◽  
Shock Proteins

Abstract Heat shock proteins (HSP) have been implicated in autoimmune diseases such as type I diabetes mellitus, systemic lupus erythematosus, and multiple sclerosis, in which T cell proliferative responses or autoantibodies towards endogenous HSP have been detected (Journal of Autoimmunity2003;20:313). HSP70 can function as an endogenous ‘danger’ signal, acting on antigen-presenting cells and critically influencing the decision between induction of tolerance and immunity upon antigen encounter (Millar et al. Nature Medicine2003; 9:1469). We studied T-cell proliferative responses and auto-antibodies to human HSP60, HSP70 and HSP90 proteins in 20 newly diagnosed aplastic anemia patients, peripheral blood was obtained (11 females, 9 males; age average 36.1±19 years). A non-isotopic immunoassay was used for BrdU incorporation into proliferative T cells and ELISA to measure HSP antibody titer. T cell proliferation was measured as the Eu-fluorescence in a time-resolved fluorometer. A positive result was defined as > 2 standard deviations (SD) from the mean of the controls. T-cell responses to HSP70 in the patient group (N=20; mean±SD Eu-fluorescence= 47,129±36,248) were significantly greater than those of the control group (N=18 healthy adult; mean Eu-fluorescence= 23,941±12,996; p=0.01). Fifty percent of the patients showed increased T cell proliferation after HSP70 stimulation compared to 5% in the control group (p=0.03). T-cell responses of the patient group to HSP90 and HSP60 were similar to those of the control group. Twenty percent of patients showed increased T cell proliferation to HSP 60 and HSP 90 stimulation compared to 5% in the control group (p=0.363). HSP antibody (IgG/A/M) seropositivity was 25% to HSP60, 50% to HSP70, and 5% to HSP90 in patients and 8% to HSP60, 0% to HSP70, and 0% to HSP90 in controls. Heightened autoimmunity to HSP70, but not to HSP60 and HSP90, is a feature of acquired aplastic anemia at presentation.

scholarly journals Anti–IL6-receptor-alpha (tocilizumab) does not inhibit human monocyte-derived dendritic cell maturation or alloreactive T-cell responses

Blood ◽  
2011 ◽  
Vol 118 (19) ◽  
pp. 5340-5343 ◽  
Author(s):  
Brian C. Betts ◽  
Erin T. St Angelo ◽  
Michael Kennedy ◽  
James W. Young
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Cell Activation ◽  
Human Monocyte ◽  
T Cell Proliferation ◽  
Dendritic Cell Activation ◽  
Alloreactive T Cell

Abstract Significant comorbidites and lethality complicate GVHD and its treatment. Targeting the cytokine milieu may improve GVHD control; and IL6 is an attractive candidate, given its role in dendritic cell activation and T-cell differentiation. Tocilizumab is a humanized mAb to IL6-receptor-α (IL6R-α), which is Food and Drug Administration–approved for treatment of rheumatoid arthritis. Mouse transplant models have demonstrated that IL6 blockade also improves GVHD scores and survival. Definitive immunologic effects of IL6 inhibition have not emerged given inconsistent alterations in regulatory T cells (Tregs) and suppression of T-cell proliferation. Despite on-target suppression of IL6R-α signaling in human monocyte-derived dendritic cells (moDCs) and T cells, our data show no effect on moDC maturation/activation, alloreactive T-cell proliferation, Treg expansion, or allogeneic Th1/Th17 responses in vitro. These findings merit attention in any clinical trials of tocilizumab for GVHD prevention or treatment and provide a rationale for evaluating more specific inhibitors of downstream JAK2/STAT3 signaling as well.

scholarly journals Human renal tubular epithelial cells suppress alloreactive T cell proliferation

2015 ◽  
Vol 179 (3) ◽  
pp. 509-519 ◽  
Author(s):  
M. W. H. J. Demmers ◽  
S. S. Korevaar ◽  
M. Roemeling-van Rhijn ◽  
T. P. P. van den Bosch ◽  
M. J. Hoogduijn ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Epithelial Cells ◽  
T Cell Proliferation ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Renal Tubular ◽  
Alloreactive T Cell
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