Allograft vasculopathy is a major limiting factor in the long-term success of cardiac transplantation. T cells play a critical role in initiation of cardiac allograft rejection and allograft ...vasculopathy. The negative T-cell costimulatory pathway PD-1:PDL1/PDL2 (programmed death-1:programmed death ligand-1/2) plays an important role in regulating alloimmune responses. We investigated the role of recipient versus donor PD-1 ligands in the pathogenesis of allograft rejection with emphasis on the role of tissue expression in regulating this alloimmune response in vivo.
We used established major histocompatibility complex class II- and class I-mismatched models of vascularized cardiac allograft rejection, blocking anti-PDL1 and anti-PDL2 antibodies, and PDL1- and PDL2-deficient mice (as donors or recipients) to study the role of the PD-1:PDL1/PDL2 pathway in chronic rejection. We also used PDL1-deficient and wild-type mice and bone marrow transplantation to generate chimeric animals that express PDL1 exclusively on either hematopoietic or parenchymal cells. PDL1 but not PDL2 blockade significantly accelerated cardiac allograft rejection in the bm12-into-B6 and B6-into-bm12 models. Although wild-type cardiac allografts survived long term, PDL1-/- donor hearts transplanted into wild-type bm12 mice exhibited accelerated rejection and vasculopathy associated with enhanced recipient T-cell alloreactivity. Interestingly, PDL1-/- recipients did not exhibit an accelerated tempo of cardiac allograft rejection. Using chimeric animals as donors, we show that PDL1 expression on cardiac tissue alone significantly prolonged graft survival compared with full PDL1-/- donor grafts in transplanted wild-type recipients.
This is the first report to demonstrate that expression of the negative costimulatory molecule PDL1 on donor cardiac tissue regulates recipient alloimmune responses, allograft rejection, and vasculopathy.
Abstract The PD-1–PDL1 pathway plays a critical role in regulating autoimmune diabetes as blockade or deficiency of PD-1 or PDL1 results in accelerated disease in NOD mice. We explored the cellular ...mechanisms involved in the regulation of these autoimmune responses by investigations involving various gene-deficient mice on the NOD background. Administration of blocking anti-PDL1 antibody to CD4+ T cell-deficient, CD8+ T cell-deficient and B cell-deficient mice demonstrated that PDL1-mediated regulation of autoreactive CD4+ and CD8+ T cells is critical for diabetes development. This concept was confirmed by adoptive transfer studies utilizing lymphocytes from BDC2.5 and 4.1 (CD4+) TCR transgenic mice and 8.3 (CD8+) TCR transgenic mice; efforts showing increased proliferation of both CD4+ and CD8+ T cells following PDL1 blockade in vivo . Furthermore, we observed that anti-PDL1-mediated acceleration is dependent upon events occurring in the pancreatic lymph nodes during early disease stages, but becomes independent of the pancreatic lymph nodes during later disease stages. These data provide strong evidence that PDL1 regulates autoimmune diabetes by limiting the expansion of CD4+ and CD8+ autoreactive T cells, and define the timing and locale of PDL1-mediated regulation of type 1 diabetes.
Background: Mortality rates for children under five years of age, and stillbirth risks, remain high in parts of sub-Saharan Africa and South Asia. The Child Health and Mortality Prevention ...Surveillance (CHAMPS) network aims to ascertain causes of child death in high child mortality settings (>50 deaths/1000 live-births). We aimed to develop a “greenfield” site for CHAMPS, based in Harar and Kersa, in Eastern Ethiopia. This very high mortality setting (>100 deaths/1000 live-births in Kersa) had limited previous surveillance capacity, weak infrastructure and political instability. Here we describe site development, from conception in 2015 to the end of the first year of recruitment. Methods: We formed a collaboration between Haramaya University and the London School of Hygiene & Tropical Medicine and engaged community, national and international partners to support a new CHAMPS programme. We developed laboratory infrastructure and recruited and trained staff. We established project specific procedures to implement CHAMPS network protocols including; death notifications, clinical and demographic data collection, post-mortem minimally invasive tissue sampling, microbiology and pathology testing, and verbal autopsy. We convened an expert local panel to determine cause-of-death. In partnership with the Ethiopian Public Health Institute we developed strategies to improve child and maternal health. Results: Despite considerable challenge, with financial support, personal commitment, and effective partnership, we successfully initiated CHAMPS. One year into recruitment (February 2020), we had received 1173 unique death notifications, investigated 59/99 MITS-eligible cases within the demographic surveillance site, and assigned an underlying and immediate cause of death to 53 children. Conclusions: The most valuable data for global health policy are from high-mortality settings, but initiating CHAMPS has required considerable resource. To further leverage this investment, we need strong, sustained, local research leadership, and to broaden the scientific remit. To support this, we have set up a new collaboration, the “Hararghe Health Research Partnership”.
Background: Mortality rates for children under five years of age, and stillbirth risks, remain high in parts of sub-Saharan Africa and South Asia. The Child Health and Mortality Prevention ...Surveillance (CHAMPS) network aims to ascertain causes of child death in high child mortality settings (>50 deaths/1000 live-births). We aimed to develop a “greenfield” site for CHAMPS, based in Harar and Kersa, in Eastern Ethiopia. This very high mortality setting (>100 deaths/1000 live-births in Kersa) had limited previous surveillance capacity, weak infrastructure and political instability. Here we describe site development, from conception in 2015 to the end of the first year of recruitment. Methods: We formed a collaboration between Haramaya University and the London School of Hygiene & Tropical Medicine and engaged community, national and international partners to support a new CHAMPS programme. We developed laboratory infrastructure and recruited and trained staff. We established project specific procedures to implement CHAMPS network protocols including; death notifications, clinical and demographic data collection, post-mortem minimally invasive tissue sampling, microbiology and pathology testing, and verbal autopsy. We convened an expert local panel to determine cause-of-death. In partnership with the Ethiopian Public Health Institute we developed strategies to improve child and maternal health. Results: Despite considerable challenge, with financial support, personal commitment, and effective partnership, we successfully initiated CHAMPS. One year into recruitment (February 2020), we had received 1173 unique death notifications, investigated 59/99 MITS-eligible cases within the demographic surveillance site, and assigned an underlying and immediate cause of death to 53 children. Conclusions: The most valuable data for global health policy are from high-mortality settings, but initiating CHAMPS has required considerable resource. To further leverage this investment, we need strong, sustained, local research leadership, and to broaden the scientific remit. To support this, we have set up a new collaboration, the “Hararghe Health Research Partnership”.
Abstract Islet allografts are subject to alloimmune and autoimmune destruction when transplanted into autoimmune prone animals or humans. The ICOS-B7h pathway plays a role in alloimmune responses, ...but its function in autoimmunity against islet cells is controversial. We investigated the role of ICOS signaling in autoimmune and alloimmune responses in NOD mice. ICOS blockade prevents development of spontaneous disease in pre-diabetic NOD mice. Furthermore, while ICOS blockade prolongs graft survival in a fully mismatched non-autoimmune islet allograft model in C57BL/6 recipients, it has no beneficial effect in reversing diabetes in models of islet transplantation in NOD mice involving autoimmunity alone or both allo- and autoimmunity. Interestingly, ICOS blockade is effective in prolonging heart allograft (not subject to tissue-specific autoimmunity) survival in NOD mice. We conclude that in islet transplantation and autoimmune diabetes, ICOS blockade can be effective in inhibiting alloimmunity and preventing autoimmunity but is ineffective in inhibiting recurrence of autoimmunity.
Anti-CD3 mAb is an effective therapy that can reverse diabetes in NOD mice and has therapeutic potential in patients with type 1 diabetes (T1D). We administered anti-CD3 to PDL1−/−.NOD mice in order ...to determine whether this treatment would reverse the development of diabetes in these mice. Mice injected with anti-CD3 neonatally were protected from T1D. However, all of these anti-CD3 treated PDL1−/−.NOD mice developed a wasting disease between 12–20 weeks of age with sudden deterioration and weight loss, leading to death within 3–5 days of development of illness. Histology revealed severe inflammation in the heart and skeletal muscles. These results suggest that deficiency of PDL1 in NOD background has the potential to lead to immune-mediated tissue damage in organs other than the pancreas, but this cannot be appreciated in PDL1−/−.NOD mice as the mice develop T1D at an early age and die from diabetes prior to manifesting other autoimmune diseases.
Abstract Anti-CD3 mAb is an effective therapy that can reverse diabetes in NOD mice and has therapeutic potential in patients with type 1 diabetes (T1D). We administered anti-CD3 to PDL1−/−.NOD mice ...in order to determine whether this treatment would reverse the development of diabetes in these mice. Mice injected with anti-CD3 mAb neonatally were protected from T1D. However, all of these anti-CD3 mAb treated PDL1−/−.NOD mice developed a wasting disease between 12 and 20 weeks of age with sudden deterioration and weight loss, leading to death within 3–5 days of development of illness. Histology revealed severe inflammation in the heart and skeletal muscles. These results suggest that deficiency of PDL1 in NOD background has the potential to lead to immune-mediated tissue damage in organs other than the pancreas, but this cannot be appreciated in PDL1−/−.NOD mice as the mice develop T1D at an early age and die from diabetes prior to manifesting other autoimmune diseases.
Background:
Mortality rates for children under five years of age, and stillbirth risks, remain high in parts of sub-Saharan Africa and South Asia. The Child Health and Mortality Prevention ...Surveillance (CHAMPS) network aims to ascertain causes of child death in high child mortality settings (>50 deaths/1000 live-births). We aimed to develop a “greenfield” site for CHAMPS, based in Harar and Kersa, in Eastern Ethiopia. This very high mortality setting (>100 deaths/1000 live-births in Kersa) had limited previous surveillance capacity, weak infrastructure and political instability. Here we describe site development, from conception in 2015 to the end of the first year of recruitment.
Methods:
We formed a collaboration between Haramaya University and the London School of Hygiene & Tropical Medicine and engaged community, national and international partners to support a new CHAMPS programme. We developed laboratory infrastructure and recruited and trained staff. We established project specific procedures to implement CHAMPS network protocols including; death notifications, clinical and demographic data collection, post-mortem minimally invasive tissue sampling, microbiology and pathology testing, and verbal autopsy. We convened an expert local panel to determine cause-of-death. In partnership with the Ethiopian Public Health Institute we developed strategies to improve child and maternal health.
Results:
Despite considerable challenge, with financial support, personal commitment and effective partnership, we successfully initiated CHAMPS. One year into recruitment (February 2020), we had received 1173 unique death notifications, investigated 59/99 MITS-eligible cases within the demographic surveillance site, and assigned an underlying and immediate cause of death to 53 children.
Conclusions:
The most valuable data for global health policy are from high mortality settings, but initiating CHAMPS has required considerable resource. To further leverage this investment, we need strong local research capacity and to broaden the scientific remit. To support this, we have set up a new collaboration, the “Hararghe Health Research Partnership”.
Background:
Mortality rates for children under five years of age, and stillbirth risks, remain high in parts of sub-Saharan Africa and South Asia. The Child Health and Mortality Prevention ...Surveillance (CHAMPS) network aims to ascertain causes of child death in high child mortality settings (>50 deaths/1000 live-births). We aimed to develop a “greenfield” site for CHAMPS, based in Harar and Kersa, in Eastern Ethiopia. This very high mortality setting (>100 deaths/1000 live-births in Kersa) had limited previous surveillance capacity, weak infrastructure and political instability. Here we describe site development, from conception in 2015 to the end of the first year of recruitment.
Methods:
We formed a collaboration between Haramaya University and the London School of Hygiene & Tropical Medicine and engaged community, national and international partners to support a new CHAMPS programme. We developed laboratory infrastructure and recruited and trained staff. We established project specific procedures to implement CHAMPS network protocols including; death notifications, clinical and demographic data collection, post-mortem minimally invasive tissue sampling, microbiology and pathology testing, and verbal autopsy. We convened an expert local panel to determine cause-of-death. In partnership with the Ethiopian Public Health Institute we developed strategies to improve child and maternal health.
Results:
Despite considerable challenge, with financial support, personal commitment, and effective partnership, we successfully initiated CHAMPS. One year into recruitment (February 2020), we had received 1173 unique death notifications, investigated 59/99 MITS-eligible cases within the demographic surveillance site, and assigned an underlying and immediate cause of death to 53 children.
Conclusions:
The most valuable data for global health policy are from high-mortality settings, but initiating CHAMPS has required considerable resource. To further leverage this investment, we need strong, sustained, local research leadership, and to broaden the scientific remit. To support this, we have set up a new collaboration, the “Hararghe Health Research Partnership”.
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