Effector mechanisms in transplant rejection

Rocha, Paulo Novis; Plumb, Troy J.; Crowley, Steven D.; Coffman, Thomas M.

doi:10.1046/j.1600-065x.2003.00090.x

Cited by 157 publications

(139 citation statements)

References 129 publications

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“…+ T cells, considered to have a major role in graft rejection [39]. In fact, a recent study has shown that allogeneic ASCs are susceptible for lysis by both cytotoxic CD8 + T cells and NK cells [40].…”

Section: Cd8mentioning

confidence: 99%

Human Mesenchymal Stem Cells Resolve Airway Inflammation, Hyperreactivity, and Histopathology in a Mouse Model of Occupational Asthma

Martínez-González

Cruz

Moreno

et al. 2014

Stem Cells and Development

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Occupational asthma (OA) is characterized by allergic airway inflammation and hyperresponsiveness, leading to progressive airway remodeling and a concomitant decline in lung function. The management of OA remains suboptimal in clinical practice. Thus, establishing effective therapies might overcome the natural history of the disease. We evaluated the ability of human adipose-tissue-derived mesenchymal stem cells (hASCs), either unmodified or engineered to secrete the IL-33 decoy receptor sST2, to attenuate the inflammatory and respiratory symptoms in a previously validated mouse model of OA to ammonium persulfate (AP). Twenty-four hours after a dermal AP sensitization and intranasal challenge regimen, the animals received intravenously 1 · 10 6 cells (either hASCs or hASCs overexpressing sST2) or saline and were analyzed at 1, 3, and 6 days after treatment. The infused hASCs induced an anti-inflammatory and restorative program upon reaching the APinjured, asthmatic lungs, leading to early reduction of neutrophilic inflammation and total IgE production, preserved alveolar architecture with nearly absent lymphoplasmacytic infiltrates, negligible smooth muscle hyperplasia/hypertrophy in the peribronchiolar areas, and baseline airway hyperreactivity (AHR) to methacholine. Local sST2 overexpression barely increased the substantial efficacy displayed by unmodified hASCs. Thus, hASCs may represent a viable multiaction therapeutic capable to adequately respond to the AP-injured lung environment by resolving inflammation, tissue remodeling, and bronchial hyperresponsiveness typical of OA.

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Section: Cd8mentioning

confidence: 99%

Human Mesenchymal Stem Cells Resolve Airway Inflammation, Hyperreactivity, and Histopathology in a Mouse Model of Occupational Asthma

Martínez-González

Cruz

Moreno

et al. 2014

Stem Cells and Development

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“…B y recognizing allogeneic MHC class I Ags and exerting cytolytic function, primarily via granzyme and perforin mechanisms, alloreactive CD8 T lymphocytes are major effectors in the allograft rejection cascade (1,2). Despite their key role in transplant immunology, however, the mechanisms of alloreactive CD8 T cell activation and memory formation are far from being elucidated.…”

mentioning

confidence: 99%

Defective Alloreactive CD8 T Cell Function and Memory Response in Allograft Recipients in the Absence of CD4 Help

Zhai

Wang

et al. 2007

The Journal of Immunology

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We have shown that alloreactive CD8 T cell activation may proceed via CD4-dependent and CD4-independent pathways, and that CD8 T cell activation in Ag-primed animals is independent of CD154 costimulation. In this report, we further analyzed the activation and function of alloreactive CD8 CTL effectors in CD4 knockout (KO) skin/cardiac allograft recipients. FACS analysis showed that alloreactive CD8 T cells were activated at a significantly reduced level in CD4 KO mice. Importantly, these helpless CD8 T cells failed to develop CD154 blockade resistance following reactivation by the same alloantigen, indicative of defective memory formation. Only transient CD4 help was required, as short-term CD4 blockade at the time of first skin graft challenge only delayed alloreactive CD8 activation, without affecting the CD8 T cell memory response to a second skin graft. Moreover, postoperative CD4 blockade had no effect on alloreactive CD8 activation. Alloreactive CD8 cells generated in the absence of CD4 help exhibited decreased effector responses. Interestingly, intragraft induction of T cell-targeted chemokines early after transplant was also dependent on CD4 help, as the induction kinetics of CXCL9 and CCL5 in CD4 KO recipients was significantly delayed, coupled with similarly delayed infiltration by CD3/CD8 cells. Remarkably, helpless CD8 cells ultimately entering the graft still displayed significantly diminished T cell effector molecules (IFN-γ, granzyme B). Thus, CD4 help is critical for alloreactive CD8 activation, function, and memory formation.

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“…9 These cells can be activated by recognizing allogeneic antigen directly or indirectly and can mediate delayed-type hypersensitivity responses to damage the allograft. 10 In addition, CD4 1 T cells can be differentiated into various subsets. CD4…”

Section: Cd4mentioning

confidence: 99%

Inhibition of Pim2-prolonged skin allograft survival through the apoptosis regulation pathway

et al. 2012

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Recently, apoptosis has been considered to be an important regulator for allograft survival. The serine/threonine kinase Pim2 has been implicated in many apoptotic pathways. In a previous study, we found that pim2 was highly expressed in CD4 1 T cells in an allograft model. Here, we further investigated the effects of Pim2 on allograft survival and the underlying mechanisms associated with apoptosis. The results showed that pim2 was overexpressed in grafts and spleens, particularly in spleen CD41 T cells when acute allorejection occurred, and correlated positively with the extent of rejection. In T cells from the spleens of naive BALB/c mice treated with 5 mM 4a (a specific inhibitor of Pim2) for 24 h, the apoptosis rate increased and the phosphorylation of BAD was decreased. Furthermore, adoptive transfer of CD41 T cells treated with 4a in vitro to allografted severe combined immunodeficiency (SCID) mice effectively prolonged allograft survival from 19.561.7 days to 3162.3 days. Moreover, the results demonstrated that the CD4 1 CD252 effector T-cell subset was the predominate expresser of the pim2 gene as compared with the CD4 1 CD25 1 regulatory T (Treg) cell subset. Alloantigen-induced CD4 1 CD25 1 T cells displayed less Foxp3 expression and a low suppression of apoptosis compared with effector CD41 CD25 2 T cells treated with 4a. Collectively, these data revealed that Pim2 facilitated allograft rejection primarily by modulating the apoptosis of effector T cells and the function of Treg cells. These data suggested that Pim2 may be an important target for in vivo anti-rejection therapies and for the ex vivo expansion of CD4 1 CD25 1 T cells.

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Effector mechanisms in transplant rejection

Cited by 157 publications

References 129 publications

Human Mesenchymal Stem Cells Resolve Airway Inflammation, Hyperreactivity, and Histopathology in a Mouse Model of Occupational Asthma

Human Mesenchymal Stem Cells Resolve Airway Inflammation, Hyperreactivity, and Histopathology in a Mouse Model of Occupational Asthma

Defective Alloreactive CD8 T Cell Function and Memory Response in Allograft Recipients in the Absence of CD4 Help

Inhibition of Pim2-prolonged skin allograft survival through the apoptosis regulation pathway

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