Monocytes show immunoregulatory capacity on CD4+ T cells in a human in-vitro model of extracorporeal photopheresis.

Extracorporeal photopheresis (ECP) is a widely used immunomodulatory therapy for the treatment of various T cell-mediated disorders such as cutaneous T cell lymphoma (CTCL), graft-versus-host disease (GvHD) or systemic sclerosis. Although clinical benefits of ECP are already well described, the underlying mechanism of action of ECP is not yet fully understood. Knowledge on the fate of CD14+ monocytes in the context of ECP is particularly limited and controversial. Here, we investigated the immunoregulatory function of ECP treated monocytes on T cells in an in-vitro ECP model. We show that ECP-treated monocytes significantly induce proinflammatory T cell types in co-cultured T cells, while anti-inflammatory T cells remain unaffected. Furthermore, we found significantly reduced proliferation rates of T cells after co-culture with ECP-treated monocytes. Both changes in interleukin secretion and proliferation were dependent on cell-contact between monocytes and T cells. Interestingly, blocking interactions of programmed death ligand 1 (PD-L1) to programmed death 1 (PD-1) in the in-vitro model led to a significant recovery of T cell proliferation. These results set the base for further studies on the mechanism of ECP, especially the regulatory role of ECP-treated monocytes.

Impact of Everolimus and Low-Dose Cyclosporin on Cytomegalovirus Replication and Disease in Pediatric Renal Transplantation.

In order to investigate the hypothesis that the mammalian target of rapamycin inhibitor everolimus (EVR) shows anticytomegalovirus (CMV) activity in pediatric patients, we analyzed the impact of EVR-based immunosuppressive therapy on CMV replication and disease in a large cohort (n = 301) of pediatric kidney allograft recipients. The EVR cohort (n = 59), who also received low-dose cyclosporin, was compared with a control cohort (n = 242), who was administered standard-dose cyclosporin or tacrolimus and an antimetabolite, mostly mycophenolate mofetil (91.7%). Multivariate analysis revealed an 83% lower risk of CMV replication in the EVR cohort than in the control cohort (p = 0.005). In CMV high-risk (donor+/recipient-) patients (n = 88), the EVR-based regimen was associated with a significantly lower rate of CMV disease (0% vs. 14.3%, p = 0.046) than the standard regimen. In patients who had received chemoprophylaxis with (val-)ganciclovir (n = 63), the CMV-free survival rates at 1 year and 3 years posttransplant (100%) were significantly (p = 0.015) higher in the EVR cohort (n = 15) than in the control cohort (n = 48; 1 year, 75.0%; 3 years, 63.3%). Our data suggest that in pediatric patients at high risk of CMV, an EVR-based immunosuppressive regimen is associated with a lower risk of CMV disease than a standard-dose calcineurin inhibitor-based regimen.

Three-year growth hormone treatment in short children with X-linked hypophosphatemic rickets: effects on linear growth and body disproportion.

CONTEXT: Children with X-linked hypophosphatemic rickets (XLH) are prone to progressive disproportionate stunting despite oral phosphate and vitamin D treatment. OBJECTIVE: Our objective was to analyze the effects of GH treatment on stature and lengths of linear body segments in short children with XLH. DESIGN, SETTINGS, AND PATIENTS: A 3-yr randomized controlled open-label GH study in short prepubertal children with XLH (n = 16) on phosphate and calcitriol treatment was conducted. A cohort of XLH patients (n = 76) on conservative treatment served as an XLH reference population. MAIN OUTCOME MEASURES: Changes in SD scores (SDS) of stature and linear body segments, i.e. sitting height, leg and arm length, and sitting height index (i.e. ratio between sitting height and stature) were the main outcome measures. RESULTS: XLH patients presented at time of enrollment with significant impairments of stature (-3.3 SDS) and linear body segments compared with healthy children. Leg length (-3.8 SDS) was most impaired, whereas sitting height (-1.7 SDS) was best preserved. The markedly elevated mean sitting height index (+3.3 SDS) reflected severe body disproportion. GH resulted in a sustained increase in linear growth (stature, +1.1 SDS; sitting height, +1.3 SDS; leg length, +0.8 SDS; arm length, +1.1 SDS; each P < 0.05 vs. baseline), whereas no significant changes were observed in controls. Mean height SDS at 3 yr did not significantly differ between groups. Sitting height index remained stable in both the GH-treated patients and in study controls but increased further in the XLH-reference population. CONCLUSIONS: The 3-yr GH treatment improved linear growth without progression of body disproportion in short children with XLH.

Mixed colorectal polyps. An immunohistologic and mucin-histochemical study.

The morphology of mixed colorectal polyps was analysed. Thirteen such polyps were found out of 2700 colorectal polyps (0.5%). Histology showed a spectrum of hyperplastic crypts from almost pure goblet cell population (two polyps) to hypermature serrated epithelium with scanty goblet cells (seven polyps). Tubular adenomas occurred in 12 polyps, and a tubulovillous adenoma was found in the largest polyp. Moderate dysplasia was seen in the five large polyps. The border between neoplastic and hyperplastic cells was usually sharp. Mucin histochemistry showed similarities between the mixed polyps and colorectal carcinomas--namely, the reduction/absence of sialomucin in both mature hyperplastic crypts and adenomatous glands. The expression of carcinoembryonic antigen within the hyperplastic crypts and within the neoplastic crypts showing moderate dysplasia was similar to that seen in colorectal carcinomas, whereas it was normal within the neoplastic crypts with low-grade dysplasia. IgA was reduced or absent in both components. Blood group antigen was found only within the adenomatous component of the largest polyp showing also moderate dysplasia.

B-cell lymphoma in transplanted liver. Clinical, histological and radiological manifestations.

An isolated, centroblastic lymphoma developed in a 25-year-old female liver transplant recipient in her liver graft a few months after transplantation. Her immunosuppressive therapy consisted of antithymocyte globulin, cyclosporin, corticosteroids and, periodically, azathioprine. Chromosome analysis showed the tumor to be of female origin, thus excluding the possibility of transfer from the male donor. The tumor cells expressed EBV nuclear antigen (EBNA). The tumor was located in the left lobe of the liver. It was successfully removed 11 months after transplantation by a hemihepatectomy following a very brief combined chemotherapy course, and was then found to be replaced by necrotic tissue. No further treatment for lymphoma was given, and the patient is now free from lymphoma 3 years after transplantation.

Duplex Doppler ultrasonography for monitoring liver transplants.

The utility of duplex Doppler ultrasonography (US) for monitoring was evaluated after 19 liver transplantations. The assessment of the resistive index (RI) of the hepatic arteries showed no significant difference in the RI measured in grafts with stable function compared with grafts with ischemic damage, acute rejection, chronic rejection, or cytomegalovirus hepatitis. Nor was there any correlation between the levels of RI and the severity of acute rejection. In 2 out of 5 liver transplants in which hepatic artery pulsations were not identified with US, hepatic artery thrombosis was found at angiography. Although high echogenicity of the parenchyma was often observed during acute rejection episodes, it was not diagnostic for rejection. Fluid collections observed around the grafts resolved spontaneously. Thus, duplex Doppler US for monitoring liver transplants is especially useful for the diagnosis of hepatic artery thrombosis. It was not helpful for the diagnosis of acute or chronic rejection.

Diagnosis of pancreatic graft rejection by duplex-Doppler ultrasonography.

The utility of duplex-Doppler ultrasonography (US) in the diagnosis of pancreatic graft rejection was evaluated in 9 patients. The examinations assessed the resistive index (RI) of arteries within the graft parenchyma, the homogeneity and echogenicity of the parenchyma, and the presence of fluid collections around the grafts. For the first 3 days after transplantation, the RI was found to be high. Subsequently, it decreased, and when the graft was in a stable condition, the mean RI was 0.63. With acute rejection episodes, the RI increased to a mean of 0.68 (p=0.002). Thus the increase in mean RI was small but significant. If serial US examinations were performed then an increase in RI, above an individual stable base-line level, was more apparent. After successful anti-rejection treatment, the RI decreased again. In 1 case with chronic rejection, the RI was found to be high, and the parenchyma was non-homogenous with high echogenicity. With pancreatitis, the RI did not change significantly. In 2 patients, fluid collections--which later resolved spontaneously--were seen around the grafts. In 1 patient, an arterial pulsation, which had been detectable previously, was found to be absent, and arterial thrombosis was confirmed at operation. In conclusion, serial duplex-Doppler US may be useful for monitoring pancreatic grafts and the RI may assist in the diagnosis of pancreatic graft rejection.

Fibromuscular dysplasia in donor kidneys--experience with three cases.

In 1987, three patients received kidney grafts bearing medial fibroplasia at our hospital. Two of the grafts were from a cadaveric donor and one was from a living related donor kidney. The vascular affection was known before transplantation. Only one of the recipients developed stenosis and hypertension. With balloon catheter dilatation, the progressive stenosis of the renal graft artery could, however, be successfully corrected.