Innate immune cellular therapeutics in transplantation

Successful organ transplantation provides an opportunity to extend the lives of patients with end-stage organ failure. Selectively suppressing the donor-specific alloimmune response, however, remains challenging without the continuous use of non-specific immunosuppressive medications, which have multiple adverse effects including elevated risks of infection, chronic kidney injury, cardiovascular disease, and cancer. Efforts to promote allograft tolerance have focused on manipulating the adaptive immune response, but long-term allograft survival rates remain disappointing. In recent years, the innate immune system has become an attractive therapeutic target for the prevention and treatment of transplant organ rejection. Indeed, contemporary studies demonstrate that innate immune cells participate in both the initial alloimmune response and chronic allograft rejection and undergo non-permanent functional reprogramming in a phenomenon termed “trained immunity.” Several types of innate immune cells are currently under investigation as potential therapeutics in transplantation, including myeloid-derived suppressor cells, dendritic cells, regulatory macrophages, natural killer cells, and innate lymphoid cells. In this review, we discuss the features and functions of these cell types, with a focus on their role in the alloimmune response. We examine their potential application as therapeutics to prevent or treat allograft rejection, as well as challenges in their clinical translation and future directions for investigation

B cells enhance early innate immune responses during bacterial sepsis

Type I interferon–responsive B cells provide early protection against bacterial sepsis

Type I interferon signaling in hematopoietic cells is required for survival in mouse polymicrobial sepsis by regulating CXCL10

Type I interferon (IFN) α/β is critical for host defense. During endotoxicosis or highly lethal bacterial infections where systemic inflammation predominates, mice deficient in IFN-α/β receptor (IFNAR) display decreased systemic inflammation and improved outcome. However, human sepsis mortality often occurs during a prolonged period of immunosuppression and not from exaggerated inflammation. We used a low lethality cecal ligation and puncture (CLP) model of sepsis to determine the role of type I IFNs in host defense during sepsis. Despite increased endotoxin resistance, IFNAR−/− and chimeric mice lacking IFNAR in hematopoietic cells display increased mortality to CLP. This was not associated with an altered early systemic inflammatory response, except for decreased CXCL10 production. IFNAR−/− mice display persistently elevated peritoneal bacterial counts compared with wild-type mice, reduced peritoneal neutrophil recruitment, and recruitment of neutrophils with poor phagocytic function despite normal to enhanced adaptive immune function during sepsis. Importantly, CXCL10 treatment of IFNAR−/− mice improves survival and decreases peritoneal bacterial loads, and CXCL10 increases mouse and human neutrophil phagocytosis. Using a low lethality sepsis model, we identify a critical role of type I IFN–dependent CXCL10 in host defense during polymicrobial sepsis by increasing neutrophil recruitment and function

A genomic storm in critically injured humans

Critical injury in humans induces a genomic storm with simultaneous changes in expression of innate and adaptive immunity genes

Pediatric pancreatic trauma: Trending toward nonoperative management?

Pancreatic trauma is rare in children and optimal care has not been defined. We undertook this study to review the cumulative experience from three centers. After obtaining Institutional Review Board approval at each site, the trauma registries of three institutions were searched for pancreatic injuries. The charts were reviewed and data pertaining to demographics, hospital course, and outcome were obtained and analyzed. During the study period, a total of 79 pancreatic injuries were noted. The most common mechanism of injury was motor vehicle crash (44%) followed by child abuse (11%) and bicycle crashes (11%). Computed tomographic (CT) scans were obtained in 95 per cent with peripancreatic fluid the most common finding. Median Injury Severity Score (ISS) was 9, whereas median organ injury score was 2, and a higher grade correlated with need for operation (P = 0.001). Pancreatic operations were performed in 32 patients, whereas nonoperative management was noted in 47 cases. We noted no differences in length of stay, age, ISS, or initial blood pressure in operative versus nonoperatively managed cases. Pancreatic injuries were rare in children with trauma. CT scans were the most common method of diagnosis. Nonoperative management appeared to be safe and was more common, especially for the lower grade injuries

“Pulling the plug”—Management of meconium plug syndrome in neonates

Background: The significance of meconium plug syndrome (MPS) is unclear but has been associated with Hirschsprung\u27s disease and magnesium tocolysis. We reviewed our experience to attempt to identify any potential association with these conditions and to review our outcomes.Methods: Using the International Classification of Diseases, Ninth revision, code for meconium obstruction, patient charts were identified during the 1998-2008 period. A total of 61 cases of MPS were found, after excluding 7 of meconium ileus. Data regarding the hospital course and outcomes were collected and analyzed.Results: Approximately 30% of patients had spontaneous resolution of the meconium plug without any treatment. Of those patients requiring treatment, contrast barium enema was used, with 97% success. Only 2 patients required surgical intervention owing to worsening distension and subsequent peritonitis. When we stratified the patients according to gestational age of \u3e36 and \u3c36 \u3ewk, contrast barium enemas were performed 2.2 ± 1.8 versus 8.6 ± 7.8 d after birth (P = 0.003), respectively, and the lower gestational age patients had a longer length of stay. Contrast barium enema was still successful in 94% of patients with a gestational age of 16% of the cases, and Hirschsprung\u27s disease was only found in 3.2% of patients.Conclusions: Patients with MPS have excellent outcomes, independent of gestational age. Contrast barium enema remains the initial diagnostic and treatment of choice for patients with MPS. Also, although previous reports have shown a link between magnesium tocolysis and Hirschsprung\u27s disease with MPS, our experience suggests otherwise

The usefulness of the upper gastrointestinal series in the pediatric patient before anti-reflux procedure or gastrostomy tube placement

Objective: Most children undergo an upper gastrointestinal study (UGI) before an anti-reflux (AR) procedure or gastrostomy tube placement (GT). Anatomic abnormalities detected by UGI are uncommon and we hypothesize that the value of routine preoperative use of this test is limited.Methods: Five hundred and seventy-two patients who underwent either an AR or GT over a 10-y period at our institution were reviewed. Data including patient demographics, indications for surgery, preoperative testing, and type of operation were collected.Results: Of the 572 cases, an UGI was performed in approximately 71%. The results were interpreted as normal in 63%, and abnormal in 37%. The most common abnormality noted was gastroesophageal reflux in approximately 80%, followed by an anatomic abnormality in 6%, most of which were expected. Of 36 anatomic abnormalities noted, only four were unexpected in the total cohort. In addition to an UGI, half of the subjects received additional evaluations that included pH probes and gastric emptying studies (GES). In these studies, 56% of pH probes and 45% of GES had findings in which reflux was noted. Compared with UGIs, these tests were significantly more likely to identify reflux in patients.Conclusion: These results suggest that the utility of an UGI before AR or GT procedures is low. Anatomic abnormalities were rare and changed clinical management in a total of four cases. A prospective trial would help to further validate these findings and help identify patients who would benefit from an UGI

Obese Patients Show A Depressed Cytokine Profile Following Severe Blunt Injury

Computational grids have been emerging as a new paradigm for solving large complex problems over the recent years. The problem space and data set are divided into smaller pieces that are processed in parallel over the grid network and reassembled upon completion. Typically, resources are logged into a resource broker that is somewhat aware of all of the participants available on the grid. The resource broker scheme can be a bottleneck because of the amount of computational power and network bandwidth needed to maintain a fresh view of the grid. In this paper, we propose to place the load of managing the network resource discovery on to the network itself: inside of the routers. In the proposed protocol, the routers contain tables for resources similar to routing tables. These resource tables map IP addresses to the available computing resource values, which are provided through a scoring mechanism. Each resource provider is scored based on the attributes they provide such as the number of processors, processor frequency, amount of memory, hard drive space, and the network bandwidth. The resources are discovered on the grid by the protocol\u27s discovery packets, which are encapsulated within the TCP/IP packets. The discovery packet visits the routers and look up in the resource tables until a satisfactory resource is found. The protocol is validated by simulations with five different deployment environments. © 2010 Springer Science+Business Media, LLC

Delayed emergency myelopoiesis following polymicrobial sepsis in neonates

Neonates have increased susceptibility to infection, which leads to increased mortality. Whether or not this as a result of implicit deficits in neonatal innate immune function or recapitulation of innate immune effector cell populations following infection is unknown. Here, we examine the process of emergency myelopoiesis whereby the host repopulates peripheral myeloid cells lost following the initial infectious insult. As early inflammatory responses are often dependent upon NF-κB and type I IFN signaling, we also examined whether the absence of MyD88, TRIF or MyD88 and TRIF signaling altered the myelopoietic response in neonates to polymicrobial sepsis. Following neonatal polymicrobial septic challenge, hematopoietic stem cell (HSC) expansion in bone marrow and the spleen were both attenuated and delayed in neonates compared with adults. Similar reductions in other precursors were observed in neonates. Similar to adult studies, the expansion of progenitor stem cell populations was also seen in the absence of MyD88 and/or TRIF signaling. Overall, neonates have impaired emergency myelopoiesis in response to sepsis compared with young adults. Despite reports that this expansion may be related to TLR signaling, our data suggest that other factors may be important, as TRIF(−/−) and MyD88(−/−) neonatal HSCs are still able to expand in response to polymicrobial neonatal sepsis

Delayed emergency myelopoiesis following polymicrobial sepsis in neonates

Neonates have increased susceptibility to infection, which leads to increased mortality. Whether or not this as a result of implicit deficits in neonatal innate immune function or recapitulation of innate immune effector cell populations following infection is unknown. Here, we examine the process of emergency myelopoiesis whereby the host repopulates peripheral myeloid cells lost following the initial infectious insult. As early inflammatory responses are often dependent upon NF-κB and type I IFN signaling, we also examined whether the absence of MyD88, TRIF or MyD88 and TRIF signaling altered the myelopoietic response in neonates to polymicrobial sepsis. Following neonatal polymicrobial septic challenge, hematopoietic stem cell (HSC) expansion in bone marrow and the spleen were both attenuated and delayed in neonates compared with adults. Similar reductions in other precursors were observed in neonates. Similar to adult studies, the expansion of progenitor stem cell populations was also seen in the absence of MyD88 and/or TRIF signaling. Overall, neonates have impaired emergency myelopoiesis in response to sepsis compared with young adults. Despite reports that this expansion may be related to TLR signaling, our data suggest that other factors may be important, as TRIF(-/-) and MyD88(-/-) neonatal HSCs are still able to expand in response to polymicrobial neonatal sepsis