The neuropeptide galanin modulates natural killer cell function.

Natural killer (NK) cells are part of the innate immune system and combat pathogens and tumors by secreting pro-inflammatory cytokines like interferon gamma (IFN-γ) and by their cytotoxic action. Galanin is a neuropeptide also expressed in peripheral tissue where it impacts several physiological functions, including inflammation. The effects of galanin are mediated via three receptors, GAL1-3. Since other neuropeptides have been shown to regulate NK cell activity, we investigated the potential of galanin to modulate human NK cell function. NK cells were isolated from human peripheral blood mononuclear cells. mRNA expression was analyzed by qRT-PCR. The dynamic mass redistribution of NK cells upon regulatory peptide stimulation was determined by label-free biochip technology. IFN-γ producing NK cells were identified by flow cytometry analysis and IFN-γ secretion was measured by ELISA. NK cell cytotoxicity was analyzed by flow cytometry via CD107a mobilization. NK cells were found to express the receptor GAL2 but not GAL1, GAL3 or galanin. Galanin per se did not affect the dynamic mass redistribution of NK cells, but significantly enhanced the response of NK cells to IL-18. Galanin significantly modulated the IFN-γ production of the CD56bright NK cell population upon IL-12 and IL-18 stimulation. Furthermore, galanin significantly modulated the IL-12 and IL-18 stimulated IFN-γ secretion. NK cell cytotoxicity was not modulated by galanin treatment. Galanin can be classified as an immunomodulatory peptide as it is able to sensitize NK cells toward specific cytokines.

Decreased NKp46 and NKG2D and elevated PD-1 are associated with altered NK-cell function in pediatric transplant patients with PTLD.

Post-transplantation lymphoproliferative disorders (PTLD) are life-threatening complications of organ transplantation caused by EBV infection and the use of chronic immunosuppression. While T-cell impairment is known to play a critical role in the immunopathogenesis of EBV complications post-transplantation, the role of NK cells is still under investigation. Here, we have characterized NK-cell phenotype and function in peripheral blood from asymptomatic pediatric thoracic transplant patients, patients with PTLD, and healthy controls. Overall, asymptomatic pediatric solid organ transplant (Tx) patients presented significant expansion of the CD56(bright) CD16(±) subset and displayed effective NK-cell function, while PTLD patients accumulated CD56(dim) CD16(-) and CD56(-) CD16(+) NK-cell subsets. In addition, NK cells from PTLD patients down-regulated NKp46 and NKG2D, and significantly up-regulated PD-1. These phenotypic changes were associated with NK functional impairment, resembling cellular exhaustion. Disrupting PD-1 inhibitory pathway improved IFN-γ release, but did not enhance cytotoxicity in PTLD patients, suggesting that these defects were partially PD-1 independent. Our results indicate the important role of NK cells during EBV surveillance post-transplantation, with implications for the immunopathogenesis of EBV complications, and suggest that monitoring NK cells in transplant patients may hold clinical value.

Enterocolitis due to simultaneous infection with rotavirus and Clostridium difficile in adult and pediatric solid organ transplantation.

Diarrhea is a well-known complication of immunosuppression but is also frequently caused by pathogens such as Clostridium difficile (CD) and rotavirus (RV). Three adult and five pediatric solid organ recipients (SORs) developed diarrhea with simultaneous identification of CD and RV. Rotavirus was identified using an immunochromatografic- or enzyme-linked immunosorbent assay; CD was identified using a rapid immunoassay or enzyme immunoassay. One adult renal, one adult kidney-pancreas, one adult liver, and five pediatric liver recipients were affected. Onset of RV/CD infection ranged from 2 weeks to 4 years posttransplant. All patients presented with enterocolitis causing significant fluid and electrolyte loss. In adults, CD was treated with metronidazole and in children with oral vancomycin. RV infection was treated with fluid/electrolyte replacement. During diarrhea, a significant rise in tacrolimus serum level was noted. All patients cleared CD. One child developed recurrent episodes of RV infection and died from bacterial sepsis; the renal recipient died 6 months posttransplant from myocardial infarction. The remaining six patients are currently alive with well-functioning grafts. Simultaneous infection with CD and RV may lead to severe diarrhea in SORs. Both pathogens should be considered in SOR presenting with diarrhea.

Malignancies of the colorectum and anus in solid organ recipients.

Patients undergoing solid organ transplantation (SOT) are at increased risk for developing malignancies due to the long term immunosuppression. Data on malignancies of the large intestine after various types of SOT are rare. A total of 3595 SOTs were performed between 1986 and 2005 at our center and retrospectively analyzed with regard to the incidence and course of malignancies of the colon, rectum, and anus. Standard immunosuppression consisted of calcineurin inhibitors in combination with azathioprine or mycophenolate mofetil and steroids with or without antithymocyte globulin or IL-2 receptor antagonist induction. A total of 206 patients (5.7%) developed malignancies. Colorectal adenocarcinoma was diagnosed in nine patients (0.25%; mean age at diagnosis 65 years) at a mean of 5.3 years after transplantation. Five patients (55%) died 7.2 years post-transplant due to cardiovascular disease (n = 4) and tumor progression (n = 1). Four patients developed anal neoplasia (0.11%) 7 years post-transplant with 100% 1-year survival. Five patients showed post-transplant lymphoproliferative disorders (PTLD) with intestinal involvement. The incidence of anal but not of colorectal cancers in our transplant recipients differed from that of immunocompetent individuals of corresponding age (0.11% vs. 0.002% and 0.25% vs. 0.3%). PTLD may involve the colon.

Rothia dentocariosa sepsis in a pediatric renal transplant recipient having post-transplant lymphoproliferative disorders.

BACKGROUND: Rothia dentocariosa (RD) is a Gram-positive rod that colonizes the human oral cavity and can cause infective endocarditis. RESULT: We report on a six-yr-old boy who underwent renal transplantation for polycystic kidney disease at the age of eight months. He developed post-transplant lymphoproliferative disorders after four yr and progressive graft failure. Following chemotherapy, the patient presented with neutropenia and sepsis. RD was isolated from blood and treatment with piperacillin/tazobactam was initiated; however, the child died because of multiorgan failure. DISCUSSION: To the best of our knowledge, this is the first case of RD sepsis in a pediatric solid organ transplant recipient.

Severe intra-abdominal infection due to Streptococcus Milleri following adjustable gastric banding.

BACKGROUND: Laparoscopic adjustable gastric banding represents a safe and effective bariatric surgical method. Nevertheless, complications such as intraabdominal infections are associated with high morbidity and mortality. CASE REPORT: A 50-year old morbidly obese female patient underwent adjustable gastric banding with the Swedish band (SAGB). After an uneventful postoperative follow-up of 2 years, she developed band infection due to colon microperforation during endoscopic polypectomy. As the causative microorgansim, Streptococcus Milleri was revealed. Band removal was required, and recovery was quite prolonged. CONCLUSION: Intra-abdominal infection with Streptococcus Milleri can cause severe and life-threatening disease. Therefore, early diagnosis and surgical intervention combined with body weight adapted antibiotic therapy for a sufficiently long period of time seems necessary. In patients with intra-abdominal implanted devices such as the SAGB who undergo endoscopic polypectomy, antibiotic prophylaxis should therefore be considered.

Listeria meningitis in transplant recipients.

INTRODUCTION: Meningitis is a rare complication following organ and stem-cell transplantation and can be caused by a variety of microorganisms. AIM: To retrospectively review the clinical course and outcome of five cases of listeriosis in four organ recipients and one stem-cell recipient during a seven-year period. PATIENTS AND METHODS: Patient records for more than 3500 patients undergoing organ or stem-cell transplantation at the university hospital of Innsbruck during a 27-year period were evaluated. Standard immunosuppression consisted of calcineurin inhibitor-based triple drug therapy with or without ATG or IL2 receptor antagonist induction. RESULTS: The first case affected a 35-year-old woman who received an allogenic bone marrow transplant for advanced breast cancer. Cases two and three related to two male heart recipients. Cases four and five were diagnosed in one male and one female renal recipient. Listeria monocytogenes was isolated from blood in two cases and from cerebrospinal fluid in three. Treatment consisted of ampicillin in all cases with the addition of tobramycin (1), TMPS (1), meropenem (2) or imipenem/cilastatin (1). The deaths of two patients were directly related to L. monocytogenes. CONCLUSIONS: Although listeriosis is a rare complication following transplantation, this infection should be ruled out in individuals presenting with neurological symptoms and fever.