Prolonged acceptance of skin grafts induced by B cells places regulatory T cells on the histopathology scene

Langier, Sheila; Galvani, Rômulo Gonçalves; Alves, Ana Paula G.; Fidelis, R.; Nunes, P.H.C.; Silva, M.H.; Castilho, Leda R.; Monteiro, João P.; Bonomo, Adriana

doi:10.1590/s0100-879x2012007500089

Cited by 5 publications

(7 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has previously been reported that the adoptive transfer of B cells suppresses the development of autoimmunity in several murine models 22 23 26 and that B cells may have a regulatory function in inducing graft survival 14 15 16 17 18 19 20 . In this study, the capacity of B cells to prolong skin transplant survival was investigated.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Diversity of gut microflora is required for the generation of B cell with regulatory properties in a skin graft model

Alhabbab

Blair

Elgueta

et al. 2015

Sci Rep

View full text Add to dashboard Cite

B cells have been reported to promote graft rejection through alloantibody production. However, there is growing evidence that B cells can contribute to the maintenance of tolerance. Here, we used a mouse model of MHC-class I mismatched skin transplantation to investigate the contribution of B cells to graft survival. We demonstrate that adoptive transfer of B cells prolongs skin graft survival but only when the B cells were isolated from mice housed in low sterility “conventional” (CV) facilities and not from mice housed in pathogen free facilities (SPF). However, prolongation of skin graft survival was lost when B cells were isolated from IL-10 deficient mice housed in CV facilities. The suppressive function of B cells isolated from mice housed in CV facilities correlated with an anti-inflammatory environment and with the presence of a different gut microflora compared to mice maintained in SPF facilities. Treatment of mice in the CV facility with antibiotics abrogated the regulatory capacity of B cells. Finally, we identified transitional B cells isolated from CV facilities as possessing the regulatory function. These findings demonstrate that B cells, and in particular transitional B cells, can promote prolongation of graft survival, a function dependent on licensing by gut microflora.

show abstract

Section: Resultsmentioning

confidence: 99%

“…However mesenchymal stem cell treatment restores Breg function, a feature which correlates with an improved clinical outcome 12 13 . In mice, there are now multiple reports that implicate a regulatory role for B cells in graft survival 14 15 16 17 18 19 20 .…”

mentioning

confidence: 99%

Diversity of gut microflora is required for the generation of B cell with regulatory properties in a skin graft model

Alhabbab

Blair

Elgueta

et al. 2015

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Transplanted mice which received syngenic T cells displayed higher Treg numbers and Treg/effector T cell ratios in all organs analyzed when compared to mice which received allogenic T cells and therefore are suffering from aGVHD ( Fig. 5A and 5B ) [ 60 ]. Mice transplanted with WT BM and T cells in the presence or absence of WT BMDC or NOD2 KO BMDC showed the same Treg absolute numbers, frequency and Treg/Teff ratio ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Mice transplanted with WT BM and T cells in the presence or absence of WT BMDC or NOD2 KO BMDC showed the same Treg absolute numbers, frequency and Treg/Teff ratio ( Fig. 5A and 5B ) [ 60 ]. The absence of differences in Treg frequencies between the various groups tested, suggests that Tregs are not involved in the mechanism by which NOD2 KO BMDC inhibits aGVHD related mortality.…”

Section: Resultsmentioning

confidence: 99%

Disease Severity and Mortality Can Be Independently Regulated in a Mouse Model of Experimental Graft versus Host Disease

et al. 2015

View full text Add to dashboard Cite

Graft versus host disease (GVHD) is the major limitation of allogeneic hematopoietic stem cell transplantation (HSCT) presenting high mortality and morbidity rates. However, the exact cause of death is not completely understood and does not correlate with specific clinical and histological parameters of disease. Here we show, by using a semi-allogeneic mouse model of GVHD, that mortality and morbidity can be experimentally separated. We injected bone marrow-derived dendritic cells (BMDC) from NOD2/CARD15-deficient donors into semi-allogeneic irradiated chimaeras and observed that recipients were protected from death. However, no protection was observed regarding clinical or pathological scores up to 20 days after transplantation. Protection from death was associated with decreased bacterial translocation, faster hematologic recovery and epithelial integrity maintenance despite mononuclear infiltration at day 20 post-GVHD induction with no skew towards different T helper phenotypes. The protected mice recovered from aGVHD and progressively reached scores compatible with healthy animals. Altogether, our data indicate that severity and mortality can be separate events providing a model to study transplant-related mortality.

show abstract

“…For GVL analysis, 10 5 P815 GFP-expressing mastocytoma cells were injected together with the BM and splenic T cell inoculum (11,12,23). Tail-to-dorsum skin transplants were performed as previously described (12,23,24).…”

Section: Mice and Transplantationsmentioning

confidence: 99%

G-CSF–Induced Suppressor IL-10+ Neutrophils Promote Regulatory T Cells That Inhibit Graft-Versus-Host Disease in a Long-Lasting and Specific Way

Perobelli

Mercadante

Galvani

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

Acute graft-versus-host disease (aGVHD) is the main complication of allogeneic hematopoietic stem cell transplantation, and many efforts have been made to overcome this important limitation. We showed previously that G-CSF treatment generates low-density splenic granulocytes that inhibit experimental aGVHD. In this article, we show that aGVHD protection relies on incoming IL-10 neutrophils from G-CSF-treated donor spleen (G-Neutrophils). These G-Neutrophils have high phagocytic capacity, high peroxide production, low myeloperoxidase activity, and low cytoplasmic granule content, which accounts for their low density. Furthermore, they have low expression of MHC class II, costimulatory molecules, and low arginase1 expression. Also, they have low IFN-γ, IL-17F, IL-2, and IL-12 levels, with increased IL-10 production and NO synthase 2 expression. These features are in accordance with the modulatory capacity of G-Neutrophils on regulatory T cell (Treg) generation. In vivo, CD25 Treg depletion shortly after transplantation with splenic cells from G-CSF-treated donors blocks suppression of aGVHD, suggesting Treg involvement in the protection induced by the G-Neutrophils. The immunocompetence and specificity of the semiallogeneic T cells, long-term after the bone marrow transplant using G-Neutrophils, were confirmed by third-party skin graft rejection; importantly, a graft-versus-leukemia assay showed that T cell activity was maintained, and all of the leukemic cells were eliminated. We conclude that G-CSF treatment generates a population of activated and suppressive G-Neutrophils that reduces aGVHD in an IL-10- and Treg-dependent manner, while maintaining immunocompetence and the graft versus leukemia effect.

show abstract

Prolonged acceptance of skin grafts induced by B cells places regulatory T cells on the histopathology scene

Cited by 5 publications

References 18 publications

Diversity of gut microflora is required for the generation of B cell with regulatory properties in a skin graft model

Diversity of gut microflora is required for the generation of B cell with regulatory properties in a skin graft model

Disease Severity and Mortality Can Be Independently Regulated in a Mouse Model of Experimental Graft versus Host Disease

G-CSF–Induced Suppressor IL-10+ Neutrophils Promote Regulatory T Cells That Inhibit Graft-Versus-Host Disease in a Long-Lasting and Specific Way

Contact Info

Product

Resources

About