scholarly journals Graft versus self (GvS) against T-cell autoantigens is a mechanism of graft–host interaction

2016 ◽  
Vol 113 (48) ◽  
pp. 13827-13832 ◽  
Author(s):  
Nora Mirza ◽  
Manfred Zierhut ◽  
Andreas Korn ◽  
Antje Bornemann ◽  
Wichard Vogel ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Transplantation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Hematopoietic Cell Transplantation ◽  
Cross Reactivity ◽  
Hematopoietic Cell ◽  
T Cell Epitopes ◽  
Graft Versus Host ◽  
Host Interaction

Graft-versus-host disease (GVHD) represents the major nonrelapse complication of allogeneic hematopoietic cell transplantation. Although rare, the CNS and the eye can be affected. In this study, manifestation in the retina as part of the CNS and T-cell epitopes recognized by the allogeneic T cells were evaluated. In 2 of 6 patients with posttransplantation retina diseases and 6 of 22 patients without ocular symptoms, antigen-specific T-cell responses against retina-specific epitopes were observed. No genetic differences between donor and recipient could be identified indicating T-cell activation against self-antigens (graft versus self). Transplantation of a preexisting immunity and cross-reactivity with ubiquitous epitopes was excluded in family donors and healthy individuals. In summary, an immunological reaction against retina cells represents a mechanism of graft-versus-host interaction following hematopoietic cell transplantation.

Molecular Mechanisms of the AICD Paradoxon in Human T Cells Revealed by an Apototic Role for CD25.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5236-5236
Author(s):  
Guenther Richter ◽  
Karin Hanewinkel ◽  
Andreas Mollweide ◽  
Stefan Burdach
Keyword(s):  
T Cell ◽  
Cell Transplantation ◽  
Microarray Analysis ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Graft Versus Host Reaction ◽  
Dual Function

Abstract The IL2R is a heterotrimeric receptor consisting of the alpha-chain (CD25) and the two signal transducing beta-, gamma-chains. CD25 monoclonal antibody (e.g. daclizumab) binding to the α-chain, blocks high affinity IL2 binding thereby preventing complete T cell activation. This opportunity to hinder T cell triggering is of ample importance in transplantation medicine and the treatment of autoimmune disease; e.g. for the prevention of an acute graft versus host reaction during allogeneic hematopoietic cell transplantation. However, gene-targeting experiments revealed, that CD25 has an important role in mediating activation induced cell death (AICD) thereby maintaining T cell homeostasis. Thus, CD25 antibodies may not only block T cell activation but may also prevent AICD attributing a dual function to IL2, which has been described by the term AICD paradoxon. The molecular mechanisms of AICD remain to be elucidated. In this study, the modulation of the genomic expression profile of human peripheral blood mononuclear cells (PBMC) with therapeutic concentrations of CD25 mAb was investigated with the aim to identify genes that are involved in T cell activation or in AICD. PBMC were stimulated with OKT3 together with recombinant IL2 in the absence or presence of 30 microgram/ml Daclizumab. Cells were incubated for 16 hrs, RNA extracted and subjected to microarray analysis on U133A gene chips (Affymetrix). Gene chip profile revealed up-regulation of 60 genes and down regulation of 36 genes respectively, by Daclizumab. Anti-CD25 treatment inhibitied cytokine genes typically expressed during T cell activation including CD40L, IL9, TNF-alpha and IFN-gamma as previously shown (e.g. Burdach et al., JCI). Surprisingly, daclizumab also blocked expression of several genes important for susceptibility to apoptosis, such as DR6. In addition, daclizumab reversed IL2-mediated repression of anti-apoptotic genes, such as TOSO. Microarray analysis of these apoptosis related genes was confirmed by RT-PCR and functional assays. In conclusion, CD25-mediated induction of pro-apoptotic as well as repression of anti-apoptotic gene clusters should be considered for future drug development of CD25-antibodies in the clinical arena: these apoptosis related gene products may represent new pharmacologic targets in hematopoietic cell transplantation as well as in the treatment of autoimmune diseases.

scholarly journals In Vitro Monitoring of Human T Cell Responses to Skin Sensitizing Chemicals—A Systematic Review

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 83
Author(s):  
Marina Aparicio-Soto ◽  
Caterina Curato ◽  
Franziska Riedel ◽  
Hermann-Josef Thierse ◽  
Andreas Luch ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cross Reactivity ◽  
T Cell Epitopes ◽  
Cell Responses ◽  
Human T Cell ◽  
The Individual

Background: Chemical allergies are T cell-mediated diseases that often manifest in the skin as allergic contact dermatitis (ACD). To prevent ACD on a public health scale and avoid elicitation reactions at the individual patient level, predictive and diagnostic tests, respectively, are indispensable. Currently, there is no validated in vitro T cell assay available. The main bottlenecks concern the inefficient generation of T cell epitopes and the detection of rare antigen-specific T cells. Methods: Here, we systematically review original experimental research papers describing T cell activation to chemical skin sensitizers. We focus our search on studies published in the PubMed and Scopus databases on non-metallic allergens in the last 20 years. Results: We identified 37 papers, among them 32 (86%) describing antigen-specific human T cell activation to 31 different chemical allergens. The remaining studies measured the general effects of chemical allergens on T cell function (five studies, 14%). Most antigen-specific studies used peripheral blood mononuclear cells (PBMC) as antigen-presenting cells (APC, 75%) and interrogated the blood T cell pool (91%). Depending on the individual chemical properties, T cell epitopes were generated either by direct administration into the culture medium (72%), separate modification of autologous APC (29%) or by use of hapten-modified model proteins (13%). Read-outs were mainly based on proliferation (91%), often combined with cytokine secretion (53%). The analysis of T cell clones offers additional opportunities to elucidate the mechanisms of epitope formation and cross-reactivity (13%). The best researched allergen was p-phenylenediamine (PPD, 12 studies, 38%). For this and some other allergens, stronger immune responses were observed in some allergic patients (15/31 chemicals, 48%), illustrating the in vivo relevance of the identified T cells while detection limits remain challenging in many cases. Interpretation: Our results illustrate current hardships and possible solutions to monitoring T cell responses to individual chemical skin sensitizers. The provided data can guide the further development of T cell assays to unfold their full predictive and diagnostic potential, including cross-reactivity assessments.

scholarly journals Strategies before, during, and after hematopoietic cell transplantation to improve T-cell immune reconstitution

Blood ◽  
2016 ◽  
Vol 128 (23) ◽  
pp. 2607-2615 ◽  
Author(s):  
Coco de Koning ◽  
Stefan Nierkens ◽  
Jaap Jan Boelens
Keyword(s):  
T Cell ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Graft Versus Host ◽  
The Right ◽  
And Function ◽  
Near Future ◽  
Lower Morbidity

Abstract T-cell immune reconstitution (IR) after allogeneic hematopoietic cell transplantation (allo-HCT) is highly variable between patients and may take several months to even years. Patients with delayed or unbalanced T-cell IR have a higher probability of developing transplantation-related morbidity, mortality, and relapse of disease. Hence, there is a need for strategies to better predict and improve IR to reduce these limitations of allo-HCT. In this review, we provide an update of current and in-near-future clinically relevant strategies before, during, and after transplantation to achieve successful T-cell IR. Potent strategies are choosing the right HCT source (eg, donor-recipient matching, cell dose, graft manipulation), individualized conditioning and serotherapy (eg, antithymocyte globulin), nutritional status, exercise, home care, modulation of microbiota, enhancing homeostatic peripheral expansion, promoting thymopoiesis, and the use of adjuvant-targeted cellular immunotherapies. Strategies to prevent graft-versus-host disease are important as well because this complication and the subsequent need for immunosuppression affects T-cell IR and function. These options aim for personalized precision transplantation, where allo-HCT therapy is designed to boost a well-balanced T-cell IR and limit complications in individual patients, resulting in overall lower morbidity and higher survival chances.

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