scholarly journals MHC class II upregulation and colocalization with Fas in experimental models of immune-mediated bone marrow failure

2011 ◽  
Vol 39 (8) ◽  
pp. 837-849 ◽  
Author(s):  
Andrew J. Erie ◽  
Leigh Samsel ◽  
Tomoiku Takaku ◽  
Marie J. Desierto ◽  
Keyvan Keyvanfar ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mhc Class Ii ◽  
Bone Marrow Failure ◽  
Class Ii ◽  
Experimental Models ◽  
Immune Mediated

scholarly journals Stratification of Antigen-presenting Cells within the Normal Cornea

2009 ◽  
Vol 1 ◽  
pp. OED.S2813 ◽  
Author(s):  
Jared E. Knickelbein ◽  
Simon C. Watkins ◽  
Paul G. Mcmenamin ◽  
Robert L. Hendricks
Keyword(s):  
Bone Marrow ◽  
Basement Membrane ◽  
Mhc Class Ii ◽  
Fluorescent Protein ◽  
Antigen Presenting Cells ◽  
Class Ii ◽  
Apical Surface ◽  
Bone Marrow Derived Cells ◽  
Green Fluorescent ◽  
Antigen Presenting

The composition and location of professional antigen presenting cells (APC) varies in different mucosal surfaces. The cornea, long considered an immune-privileged tissue devoid of APCs, is now known to host a heterogeneous network of bone marrow-derived cells. Here, we utilized transgenic mice that express enhanced green fluorescent protein (EGFP) from the CD 11c promoter (pCD11c) in conjunction with immunohistochemical staining to demonstrate an interesting stratification of APCs within non-inflamed murine corneas. pCD11c+ dendritic cells (DCs) reside in the basal epithelium, seemingly embedded in the basement membrane. Most DCs express MHC class II on at least some dendrites, which extend up to 50 μm in length and traverse up 20 μm tangentially towards the apical surface of the epithelium. The DC density diminishes from peripheral to central cornea. Beneath the DCs and adjacent to the stromal side of the basement membrane reside pCD11c–CD11b+ putative macrophages that express low levels of MHC class II. Finally, MHC class II–pCD11c–CD11b+ cells form a network throughout the remainder of the stroma. This highly reproducible stratification of bone marrow-derived cells is suggestive of a progression from an APC function at the exposed corneal surface to an innate immune barrier function deeper in the stroma.

scholarly journals The Effectiveness of Rapamycin Combined with Eltrombopag in Murine Models of Immune-Mediated Bone Marrow Failure

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-11
Author(s):  
Rong Fu ◽  
Shaoxue Ding ◽  
Xiaowei Liang ◽  
Tian Zhang ◽  
Zonghong Shao
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Standard Dose ◽  
Bone Marrow Failure ◽  
Statistical Significance ◽  
Murine Models ◽  
Immune Mediated ◽  
Tnf Α ◽  
Significant Difference ◽  
Ifn Γ

Recent research has found that Rapamycin (Rapa) was an effective therapy in mouse models of immune-mediated bone marrow failure. However, it has not achieved satisfactory effect in clinical application. At present, many studies have confirmed that Eltrombopag (ELT) combined with IST can improve the curative effect of AA patients. Then whether Rapa combined with Elt in the treatment of AA will be better than single drug application. In this study, we tested efficacy of Rapa combined with Elt as a new treatment in mouse models of immune-mediated bone marrow failure. Compared with AA group, the whole blood cell count of Rapa+Elt group increased significantly (Figure 1A) (P<0.05). Survival of mice of Rapa+Elt group was significantly higher than that in the Rapa group (p <0.01)(Figure 1B).There was no obvious difference in the numbers of NK cells and their subsets were noted in Rapa group,CsA group and Rapa+Elt group.The expression of NKG2D on peripheral functional NK cells was up-regulated in CsA group, Rapa group and Rapa+Elt group compared with AA group (P<0.05). But there was no significant difference between effect of Rapa and CsA on the function of NK cells (Figure 1C).When Rapa combined with Elt, the expression of CD80 and CD86 are down-regulated more compared to Rapa group, but there is no statistical significance. Although these results suggested that Rapa+Elt had no statistical significance effect on numbers of mDC and expression of its functional molecule CD80 and CD86, the combined therapy still indicated that there is a potential synergy with immunosuppressant on AA mice to improve its outcome (Figure 1D).The results showed that CD4+/CD8+ ratio in CsA group, Rapa group, Rapa + Elt group had an obvious elevation than AA group (all P<0.05). But there were no significant difference among the three groups on the CD4+/CD8+ ratio (Figure 1E,1F). As for INF-gamma, Rapa can reduce the secretion of IFN-γ from CD8+T cells with efficacy similar to that of the standard dose of CsA, and had a better outcome when combined with Elt in bone marrow failure mice (Figure 1E,1G).CsA group, Elt group, Rapa group, Rapa + Elt group showed notable increased ratio of Tregs compared with AA group, among which there were only Rapa group, Rapa + Elt group showed statistical significance(P<0.05). for IL-10/Tregs ratio, Rapa group and Rapa +Elt group were superior to than CsA group(P<0.05) (Figure 1H,1I).Rapa+Elt group and Rapa showed more lower level of IFN-γ compared with CsA group, and there was significant difference in Rapa+Elt group(P<0.05). As for IL-10, IL-12p70, IL-2, IL-6, KC/GRO and TNF-α, the Rapa+Elt group showed more significant effect than Rapa or Elt alone(Figure1J). Thus, Rapa+Elt significantly down-regulated cytokines related to Th1 immune responses, such as IFN-γ, and upregulated cytokines related to Th2 immune responses, such as IL-10. To some extent, Rapa combined with Elt has a synergistic effect with CsA and Rapa alone in AA treatment. Conclusions In this study, Although Rapa combined with Elt had no significant improvement effect on the number and function of NK cells and their subsets, mDCs, and CD4+/CD8+ ratio in AA mice compared with Rapa alone, the Rapa+Elt can increase the secretion of IL-10 of Tregs and the number of Tregs, but has no significant effect on the number of Treg cells compared to with Rapa alone. Compared with AA group, the level of plasma IFN-γ, IL-2 and TNF-α decreased significantly (P<0.05), but IL-10, IL-4, IL-5 and IL-1β increased significantly in Rapa group(P<0.05). As for IL-10, IL-12p70, IL-2, IL-6, KC/GRO and TNF-α, the Rapa+Elt group showed more significant effect than Rapa alone. intervention treatment with Rapa in combination Elt in the AA mouse model more obviously ameliorated pancytopenia, improved bone marrow cellularity, and extended animal survival in a manner comparable to the standard dose of CsA and Rapa alone. Combination therapy support potential clinical utility in aplastic anemia treatment, which may further improve the efficacy of AA patients. Keywords: Rapamycin, Eltrombopag, murine models, bone marrow failure Figure 1 Disclosures No relevant conflicts of interest to declare.

scholarly journals The role of the Th1 transcription factor T-bet in a mouse model of immune-mediated bone-marrow failure

Blood ◽  
2010 ◽  
Vol 115 (3) ◽  
pp. 541-548 ◽  
Author(s):  
Yong Tang ◽  
Marie J. Desierto ◽  
Jichun Chen ◽  
Neal S. Young
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Transcription Factor ◽  
Transforming Growth Factor ◽  
Bone Marrow Failure ◽  
Critical Role ◽  
Interferon Γ ◽  
Interleukin 17 ◽  
Immune Mediated

Abstract The transcription factor T-bet is a key regulator of type 1 immune responses. We examined the role of T-bet in an animal model of immune-mediated bone marrow (BM) failure using mice carrying a germline T-bet gene deletion (T-bet−/−). In comparison with normal C57BL6 (B6) control mice, T-bet−/− mice had normal cellular composition in lymphohematopoietic tissues, but T-bet−/− lymphocytes were functionally defective. Infusion of 5 × 106 T-bet−/− lymph node (LN) cells into sublethally irradiated, major histocompatibility complex–mismatched CByB6F1 (F1) recipients failed to induce the severe marrow hypoplasia and fatal pancytopenia that is produced by injection of similar numbers of B6 LN cells. Increasing T-bet−/− LN-cell dose to 10 to 23 × 106 per recipient led to only mild hematopoietic deficiency. Recipients of T-bet−/− LN cells had no expansion in T cells or interferon-γ–producing T cells but showed a significant increase in Lin−Sca1+CD117+CD34− BM cells. Plasma transforming growth factor-β and interleukin-17 concentrations were increased in T-bet−/− LN-cell recipients, possibly a compensatory up-regulation of the Th17 immune response. Continuous infusion of interferon-γ resulted in hematopoietic suppression but did not cause T-bet−/− LN-cell expansion or BM destruction. Our data provided fresh evidence demonstrating a critical role of T-bet in immune-mediated BM failure.

scholarly journals The importance of MHC class II in allogeneic bone marrow transplantation and chimerism-based solid organ tolerance in a rat model

PLoS ONE ◽  
2020 ◽  
Vol 15 (5) ◽  
pp. e0233497
Author(s):  
Kai Timrott ◽  
Oliver Beetz ◽  
Felix Oldhafer ◽  
Jürgen Klempnauer ◽  
Florian W. R. Vondran ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Mhc Class Ii ◽  
Rat Model ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Class Ii ◽  
Allogeneic Bone Marrow ◽  
Solid Organ ◽  
Allogeneic Bone

Sirolimus promotes tolerance for donor and recipient antigens after MHC class II disparate bone marrow transplantation in rats

2007 ◽  
Vol 35 (1) ◽  
pp. 164-170 ◽  
Author(s):  
Mark D. Jäger ◽  
Jian Y. Liu ◽  
Kai F. Timrott ◽  
Felix C. Popp ◽  
Oliver Stoeltzing ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Mhc Class Ii ◽  
Marrow Transplantation ◽  
Class Ii

Selection of Unrelated Bone Marrow Donors: Does the Current Procedure Warrant Complete MHC Class II Identity?

1992 ◽  
Vol 19 (3) ◽  
pp. 127-129
Author(s):  
T.H. Eiermann ◽  
M. Ballas ◽  
J. Fakler ◽  
C. Müller ◽  
A. Wölpl ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Selection Of ◽  
Current Procedure

scholarly journals Aplastic anemia: immunosuppressive therapy in 2010

2011 ◽  
Vol 3 (2s) ◽  
pp. 7 ◽  
Author(s):  
Antonio M. Risitano ◽  
Fabiana Perna
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
State Of The Art ◽  
Bone Marrow Failure ◽  
Standards Of Care ◽  
Bone Marrow Failure Syndrome ◽  
Clinical Observations ◽  
Immune Mediated ◽  
Experimental Works ◽  
Current Standards

Acquired aplastic anemia (AA) is the typical bone marrow failure syndrome characterized by an empty bone marrow; an immune-mediated pathophysiology has been demonstrated by experimental works as well as by clinical observations. Immunusuppressive therapy (IST) is a key treatment strategy for aplastic anemia; since 20 years the standard IST for AA patients has been anti-thymocyte globuline (ATG) plus cyclosporine A (CyA), which results in response rates ranging between 50% and 70%, and even higher overall survival. However, primary and secondary failures after IST remain frequent, and to date all attempts aiming to overcome this problem have been unfruitful. Here we review the state of the art of IST for AA in 2010, focusing on possible strategies to improve current treatments. We also discuss very recent data which question the equality of different ATG preparations, leading to a possible reconsideration of the current standards of care for AA patients.

Donor CD4+CD25+ T Cells Require Syngeneic MHC Class II for Initial Support of MHC-Mismatched Hematopoietic Engraftment.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 251-251 ◽  
Author(s):  
Alan Hanash ◽  
Robert B. Levy
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Allogeneic Bone Marrow Transplantation ◽  
Class Ii ◽  
Allogeneic Bone ◽  
Inherited Disorders ◽  
Donor Chimerism

Abstract Despite the potential to cure both acquired and inherited disorders involving the hematopoietic compartment, application of allogeneic bone marrow transplantation (BMT) is limited by the frequent and severe outcome of Graft vs. Host Disease (GVHD). Unfortunately, efforts to reduce GVHD by purging the donor graft of T cells have resulted in poor engraftment and elevated disease recurrence. Alternative cell populations capable of supporting allogeneic engraftment without inducing GVHD could increase the potential for donor-recipient matching and decrease treatment associated risks. We have observed that GVHD-suppressive donor CD4+CD25+ T cells are capable of supporting allogeneic hematopoietic engraftment, as demonstrated by initial donor progenitor activity and long-term chimerism and tolerance. Using a murine MHC mismatched model transplanting 0.5–2x106 GFP+ C57BL/6 (B6) T cell-depleted bone marrow cells into 7.0 Gy sublethally irradiated BALB/c recipients, splenic CFU assessment demonstrated that co-transplantation of 1x106 B6 CD4+CD25+ T cells lead to increased donor lineage-committed GM (p<.01) and multi-potential HPP (p<.05) progenitors seven days post-BMT compared to transplantation of BM alone. Furthermore, co-transplantation of CD4+CD25+ T cells lead to lymphoid and myeloid chimerism in peripheral blood (lineage specific mean donor chimerism ± SE: B220, 67.7±15.2 vs. 0.3±0.3; CD4, 38.3±10.5 vs.0.9±0.9; CD8, 48.3±11.0 vs. 1.0±1.0; Mac-1, 58.8±16.5 vs. 0.3±0.3) and the presence of donor GM and HPP progenitors in recipient marrow two months post-BMT (mean CFU chimerism ± SE: CFU-GM, 54.5±12.8 vs. 0.0; CFU-HPP, 63.0±17.8 vs.0.0). Donor chimerism persisted six months post-BMT and was associated with tolerance to donor and host antigens by acceptance of donor and host skin grafts >50 days post-homotopic grafting. Characterization of the initial invents of engraftment support demonstrated that augmentation of donor progenitors did not require CD4+CD25+ T cell IL-10, as co-transplantation of B6-wt and B6-IL-10−/− CD4+CD25+ T cells both significantly increased total CFU-GM (mean CFU±SE: BM alone, 657.5±248.2; BM + wt, 1972±331.5; BM + IL-10−/−, 1965±401.7; both p<.05 vs. BM alone). Assessment of the antigenic requirements for activation of progenitor support demonstrated that donor CD4+CD25+ T cells did not require alloreactivity to support progenitors, as BALB/c x B6 F1 CD4+CD25+ T cells significantly increased B6 CFU-GM in BALB/c recipients (p<.001 vs. BM alone). However, B6 CD4+CD25+ T cells failed to augment C3H/HeJ CFU-GM in BALB/c recipients (p>.05 vs. BM alone), suggesting that donor CD4+CD25+ T cells might require recognition of syngeneic MHC for progenitor support. Indeed, augmentation of donor CFU-GM was abrogated when B6 CD4+CD25+ T cells were co-transplanted with B6-MHC class II−/− marrow into BALB/c recipients (p>.05 vs. BM alone). In conclusion, donor CD4+CD25+ T cells capable of promoting long-term engraftment and tolerance do not require IL-10 for support of initial donor progenitor activity, however progenitor support does require co-transplantation with syngeneic MHC class II expressing marrow. Donor CD4+CD25+ T cells may thus represent a useful alternative to unfractionated T cells for promotion of engraftment following allogeneic hematopoietic transplantation.

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