Alteration of Innate Immunity by Donor IL-6 Deficiency in a Presensitized Heart Transplant Model

Engraftment of IL-6 deficient donor into wild-type recipient could significantly improve allograft survival through T cell lineage particularly regulatory T cells (Tregs) in non-sensitized transplant host. However, its effect on innate immune responses remains uncertain. Our data revealed that donor IL-6 deficiency significantly increased infiltration of two subsets of MDSCs (CD11b+Gr1+myeloid-derived suppressor cells), CD11b+Gr1-low and CD11b+Gr1-int with strong immunosuppression activity in the transplanted graft. It resulted in a dramatic increase of CD11b+Gr1-low frequency and a significant decrease of the frequency of CD11b+Gr1-high and CD4-CD8-NK1.1+ cells in the recipient’s spleen. Unexpectedly, donor IL-6 deficiency could not significantly reduce macrophage frequency irrespective of in the host’s spleen or graft. Taken together, suppression of innate immune effector cells and enhanced activity of regulatory MDSCs contributed to tolerance induction by blockade of IL-6 signaling pathway. The unveiled novel mechanism of targeting IL-6 might shed light on clinical therapeutic application in preventing accelerated allograft rejection for those pre-sensitized transplant recipients

Attitudes toward live and postmortem kidney donation: a survey of chinese medical students

OBJECTIVES: As the gap between supply and demand for donor organs is increasing, we sought to clarify the knowledge and attitudes regarding living-organ donation among Chinese medical students and analyze their incentives and influencing factors. MATERIALS AND METHODS: Data were collected from Chinese medical students using a standardized questionnaire. RESULTS: Of 320 surveyed participants, 261 participants (81.6%) said they would consider donating their live kidney organ, and 262 participants (81.9%) were willing to donate posthumously. Although 177 participants (55.7%) confirmed current regulations on posthumous organ donation, only 85 participants (26.7%) could correctly identify the regulations on live organ donation in China. Gender differences were not significantly associated with willingness to donate a kidney, whereas religion and socioeconomic status of the respondents were significantly associated with willingness to donate a live or posthumous kidney. CONCLUSIONS: Among well-informed, young, healthy, and economically well-off Chinese male and female medical students, most were willing to be live kidney donors. Religion and socioeconomic status may affect the decision-making process for organ disposition

Experiences and Challenges of Emerging Online Health Services Combating COVID-19 in China: Retrospective, Cross-Sectional Study of Internet Hospitals

BackgroundInternet-based online virtual health services were originally an important way for the Chinese government to resolve unmet medical service needs due to inadequate medical institutions. Its initial development was not well received. Then, the unexpected COVID-19 pandemic produced a tremendous demand for telehealth in a short time, which stimulated the explosive development of internet hospitals. The Second Affiliated Hospital of Zhejiang University (SAHZU) has taken a leading role in the construction of internet hospitals in China. The pandemic triggered the hospital to develop unique research on health service capacity under strict quarantine policies and to predict long-term trends. ObjectiveThis study aims to provide policy enlightenment for the construction of internet-based health services to better fight against COVID-19 and to elucidate future directions through an in-depth analysis of 2 years of online health service data gleaned from SAHZU’s experiences and lessons learned. MethodsWe collected data from SAHZU Internet Hospital from November 1, 2019, to September 16, 2021. Data from over 900,000 users were analyzed with respect to demographic characteristics, demands placed on departments by user needs, new registrations, and consultation behaviors. Interrupted time series (ITS) analysis was adopted to evaluate the impact of this momentous emergency event and its long-term trends. With theme analysis and a defined 2D model, 3 investigations were conducted synchronously to determine users’ authentic demands on online hospitals. ResultsThe general profile of internet hospital users is young or middle-aged women who live in Zhejiang and surrounding provinces. The ITS model indicated that, after the intervention (the strict quarantine policies) was implemented during the outbreak, the number of internet hospital users significantly increased (β_2=105.736, P<.001). Further, long-term waves of COVID-19 led to an increasing number of users following the outbreak (β_3=0.167, P<.001). In theme analysis, we summarized 8 major demands by users of the SAHZU internet hospital during the national shutdown period and afterwards. Online consultations and information services were persistent and universal demands, followed by concerns about medical safety and quality, time, and cost. Users’ medical behavior patterns changed from onsite to online as internet hospital demands increased. ConclusionsThe pandemic has spawned the explosive growth of telehealth; as a public tertiary internet hospital, the SAHZU internet hospital is partially and irreversibly integrated into the traditional medical system. As we shared the practical examples of 1 public internet hospital in China, we put forward suggestions about the future direction of telehealth. Vital experience in the construction of internet hospitals was provided in the normalization of COVID-19 prevention and control, which can be demonstrated as a model of internet hospital management practice for other medical institutions

Kaplan-Meier cardiac graft survival curve.

<p>Heterotopic abdominal heart transplantation was performed by using standard procedure. All transplanted mice were monitored every day until graft rejection, defined as the cessation of palpable cardiac activity. Although only three symbols of “triangle” are observed for group (WT B6B/c), two grafts survived for 7 days and two grafts survived for 8 days. It implies that each “triangle” on day 7 (60% remained to survive on day 7) and day 8 (20% remained to survive on day 8) represents two grafts. Graft survival of the allogeneic control group (C57BL/6BALB/c, n=5) is equivalent to IL-6 deficiency donor graft (IL-6KOBALB/c) treated with anti-CD25 mAb (n=5) (Mantel-Cox Test, p=0.17; Gehan-Breslow-Wilcoxon Test, p=0.28), whereas IL-6 deficiency donor graft survival (IL-6KOBALB/c) treated with iso-IgG (n=5) was significantly prolonged (Mantel-Cox Test, p=0.012; Gehan-Breslow-Wilcoxon Test, p=0.0031) in comparison to allogeneic control group.</p

(A) The frequency of MDSCs, CD4-CD8-NK1.1+, F4/80+ cells within cardiac graft of the transplant recipient. Graft-infiltrating these innate immune cells were collected for fluorochrome-labeling and subject to FACS analysis on day 3 after transplant. (B) Statistical analysis was performed for the groups G5 (n=3) and G6 (n=4). *p<0.05, **p<0.01.

<p>(A) The frequency of MDSCs, CD4-CD8-NK1.1+, F4/80+ cells within cardiac graft of the transplant recipient. Graft-infiltrating these innate immune cells were collected for fluorochrome-labeling and subject to FACS analysis on day 3 after transplant. (B) Statistical analysis was performed for the groups G5 (n=3) and G6 (n=4). *p<0.05, **p<0.01.</p

Graft histology and immunohistochemical analysis of grafts.

<p>(A) The heart transplanted recipients were sacrificed at day 9 after surgery. Allogeneic grafts were harvested, stained with H&E to assess inflammation and lymphocytes infiltration between different groups under microscope, as described in the Methods section. The figure shows that a mild leukocytes infiltration was observed in the IL-6 deficient donors (G1) (n=2), while a pronouncedly infiltration of leukocytes and preserved cardiac architecture were observed in the subepicardial area of the IL-6KO grafts treated by anti-CD25 mAb (PC61) (G2) (n=2) and wild-type allografts (G3) (n=2) without any treatment. (B) Grafts specimens harvested at day 9 post-transplant were snap-frozen into Tissue Tec and stained for Gr-1 protein as described in the Materials and Methods section. Immunohistochemical sections showed that depletion of Treg cells using anti-CD25 mAb (PC61) remarkably caused an infiltration of Gr-1+ cells in the IL-6 deficient grafts, which is similar to acutely rejected wild-type hearts. A mild subepicardial Gr-1+ cells infiltration was found within IL-6KO grafts without any treatment. Original magnification ╳ 40.</p

Administration of anti-CD25 mAb (PC61) depleted CD4+CD25+Foxp3+ cells (n=2).

<p>Peripheral blood CD4+CD25+Foxp3+ T cells was analyzed through flow cytometry at day -3 (pre-administration of anti-CD25 monoclonal antibody), day 0 (transplant surgery), day 3, and day 9 post-transplant surgery. Administration of anti-CD25mAb 3 days before transplant surgery resulted in a continuous decrease of frequency of peripheral CD4+CD25+Foxp3+ T cells (12.4% on day -3, 2.78% on day 0, 0.64% on day 3). On day 9, the frequency of peripheral CD4+CD25+Foxp3+ T cells reactively increased owing to acute rejection event.</p