Bone marrow chimerism as a strategy to produce tolerance in solid organ allotransplantation

2016 ◽  
Vol 21 (6) ◽  
pp. 595-602
Author(s):  
Min Hu ◽  
Stephen I. Alexander ◽  
Shounan Yi
Author(s):  
Joanna Cwykiel ◽  
Arkadiusz Jundzill ◽  
Aleksandra Klimczak ◽  
Maria Madajka-Niemeyer ◽  
Maria Siemionow

AbstractThis study evaluated the efficacy of donor recipient chimeric cell (DRCC) therapy created by fusion of donor and recipient derived bone marrow cells (BMC) in chimerism and tolerance induction in a rat vascularized composite allograft (VCA) model. Twenty-four VCA (groin flaps) from MHC-mismatched ACI (RT1a) donors were transplanted to Lewis (RT1l) recipients. Rats were randomly divided into (n = 6/group): Group 1—untreated controls, Groups 2—7-day immunosuppression controls, Group 3—DRCC, and Group 4—DRCC with 7-day anti-αβTCR monoclonal antibody and cyclosporine A protocol. DRCC created by polyethylene glycol-mediated fusion of ACI and Lewis BMC were cultured and transplanted (2–4 × 106) to VCA recipients via intraosseous delivery route. Flow cytometry assessed peripheral blood chimerism while fluorescent microscopy and PCR tested the presence of DRCC in the recipient’s blood, bone marrow (BM), and lymphoid organs at the study endpoint (VCA rejection). No complications were observed after DRCC intraosseous delivery. Group 4 presented the longest average VCA survival (79.3 ± 30.9 days) followed by Group 2 (53.3 ± 13.6 days), Group 3 (18 ± 7.5 days), and Group 1 (8.5 ± 1 days). The highest chimerism level was detected in Group 4 (57.9 ± 6.2%) at day 7 post-transplant. The chimerism declined at day 21 post-transplant and remained at 10% level during the entire follow-up period. Single dose of DRCC therapy induced long-term multilineage chimerism and extended VCA survival. DRCC introduces a novel concept of customized donor-recipient cell-based therapy supporting solid organ and VCA transplants.


1995 ◽  
Vol 59 (4) ◽  
pp. 616-620 ◽  
Author(s):  
Adriana Zeevi ◽  
Mary Pavlick ◽  
Susan Lombardozzi ◽  
Richard Banas ◽  
Orit Pappo ◽  
...  

Medicina ◽  
2018 ◽  
Vol 54 (2) ◽  
pp. 27 ◽  
Author(s):  
Wojciech Wołyniec ◽  
Małgorzata Sulima ◽  
Marcin Renke ◽  
Alicja Dębska-Ślizień

Introduction. The immunosuppression used after transplantation (Tx) is associated with an increased risk of opportunistic infections. In Europe, parasitic infections after Tx are much less common than viral, bacterial and fungal ones. However, diseases caused by parasites are very common in tropical countries. In the last years the number of travellers with immunosuppression visiting tropical countries has increased. Methods. We performed a literature review to evaluate a risk of parasitic infections after Tx in Europe. Results. There is a real risk of parasitic infection in patients after Tx travelling to tropical countries. Malaria, leishmaniasis, strongyloidiasis and schistosomiasis are the most dangerous and relatively common. Although the incidence of these tropical infections after Tx has not increased, the course of disease could be fatal. There are also some cosmopolitan parasitic infections dangerous for patients after Tx. The greatest threat in Europe is toxoplasmosis, especially in heart and bone marrow recipients. The most severe manifestations of toxoplasmosis are myocarditis, encephalitis and disseminated disease. Diarrhoea is one of the most common symptoms of parasitic infection. In Europe the most prevalent pathogens causing diarrhoea are Giardia duodenalis and Cryptosporidium. Conclusions. Solid organ and bone marrow transplantations, blood transfusions and immunosuppressive treatment are associated with a small but real risk of parasitic infections in European citizens. In patients with severe parasitic infection, i.e., those with lung or brain involvement or a disseminated disease, the progression is very rapid and the prognosis is bad. Establishing a diagnosis before the patient’s death is challenging.


1995 ◽  
Vol 59 (4) ◽  
pp. 616-620 ◽  
Author(s):  
Adriana Zeevi ◽  
Mary Pavlick ◽  
Susan Lombardozzi ◽  
Richard Banas ◽  
Orit Pappo ◽  
...  

2005 ◽  
Vol 80 (11) ◽  
pp. 1541-1545 ◽  
Author(s):  
Jonathan D. Powell ◽  
Courtney Fitzhugh ◽  
Elizabeth M. Kang ◽  
Mathew Hsieh ◽  
Ronald H. Schwartz ◽  
...  

Blood ◽  
2018 ◽  
Vol 131 (19) ◽  
pp. 2111-2119 ◽  
Author(s):  
Rafael Kramann ◽  
Rebekka K. Schneider

Abstract Myofibroblasts are fibrosis-driving cells and are well characterized in solid organ fibrosis, but their role and cellular origin in bone marrow fibrosis remains obscure. Recent work has demonstrated that Gli1+ and LepR+ mesenchymal stromal cells (MSCs) are progenitors of fibrosis-causing myofibroblasts in the bone marrow. Genetic ablation of Gli1+ MSCs or pharmacologic targeting of hedgehog (Hh)-Gli signaling ameliorated fibrosis in mouse models of myelofibrosis (MF). Moreover, pharmacologic or genetic intervention in platelet-derived growth factor receptor α (Pdgfrα) signaling in Lepr+ stromal cells suppressed their expansion and ameliorated MF. Improved understanding of cellular and molecular mechanisms in the hematopoietic stem cell niche that govern the transition of MSCs to myofibroblasts and myofibroblast expansion in MF has led to new paradigms in the pathogenesis and treatment of MF. Here, we highlight the central role of malignant hematopoietic clone-derived megakaryocytes in reprogramming the hematopoietic stem cell niche in MF with potential detrimental consequences for hematopoietic reconstitution after allogenic stem cell transplantation, so far the only therapeutic approach in MF considered to be curative. We and others have reported that targeting Hh-Gli signaling is a therapeutic strategy in solid organ fibrosis. Data indicate that targeting Gli proteins directly inhibits Gli1+ cell proliferation and myofibroblast differentiation, which results in reduced fibrosis severity and improved organ function. Although canonical Hh inhibition (eg, smoothened [Smo] inhibition) failed to improve pulmonary fibrosis, kidney fibrosis, or MF, the direct inhibition of Gli proteins ameliorated fibrosis. Therefore, targeting Gli proteins directly might be an interesting and novel therapeutic approach in MF.


2020 ◽  
pp. 684-705
Author(s):  
Maha Albur ◽  
Alasdair MacGowan ◽  
Roger G. Finch

The practice of medicine changed dramatically with the availability of effective antimicrobial agents. Often fatal diseases, such as infective endocarditis, became treatable; much minor community infectious morbidity became readily controlled; for example, urinary tract infection; many surgical procedures became much safer, and developments in solid organ and bone marrow transplantation became possible. However, the very success of antimicrobial chemotherapy has led to anti-infective overuse and misuse. In some countries, antibiotics are freely available to the public for purchase ‘over the counter’, with few controls or guidance to ensure their safe and effective use. In many others there are poorly developed antimicrobial stewardship programmes. The emergence and spread of antimicrobial resistance worldwide and the decline in development and licensing of new antimicrobials over the last 30 years has threatened the future successful treatment of bacterial infections.


PLoS ONE ◽  
2020 ◽  
Vol 15 (5) ◽  
pp. e0233497
Author(s):  
Kai Timrott ◽  
Oliver Beetz ◽  
Felix Oldhafer ◽  
Jürgen Klempnauer ◽  
Florian W. R. Vondran ◽  
...  

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