Pretransplant immunomodulation of highly sensitized small bowel transplant candidates with intravenous immune globulin

Presence of preformed lymphocytotoxic antibodies may represent a barrier to isolated intestinal transplantation (IITx). We developed an intravenous immunoglobulins (IVIg) based desensitization protocol for candidates with high panel-reactive antibodies (PRA). Six patients with a mean PRA of 72+/-22% were included in a four-level (L) protocol with escalating doses of IVIg (L1, L2), addition of mycophenolate mofetil (MMF) or plasmapheresis (L3); and anti-CD20 (Rituximab) (L4). Four of six candidates improved their PRAs (from a mean of 66.2% to 25.5%; P=0.01) and were successfully transplanted. At a mean follow-up of 8 months, number and severity of rejection episodes of protocol patients did not differ from patients with low PRA transplanted during the same period. These data support the use of IVIg to desensitize patients waiting for IITx. It increases the applicability of IITx, and reduces the waiting time and mortality on the waiting list with outcomes comparable to nonsensitized recipients.     

Evaluation of p53 nuclear accumulation in low- and high-grade (WHO/ISUP classification) transitional papillary carcinomas of the bladder for tumor recurrence and progression

OBJECTIVES: To evaluate the association of p53 nuclear accumulation with recurrence and progression in transitional cell carcinomas of the bladder and to examine the distribution of p53 in low-grade and high-grade transitional cell carcinomas according to the World Health Organization/International Society of Urological Pathology classification. PATIENTS AND METHODS: Nuclear accumulations of p53 were examined in a total of 99 patients with transitional cell carcinoma between May 1995 and October 1999. The mean age was 64 years. There were 94 (95%) men and 5 (5%) women. Following resection, surgical specimens were examined, and p53 accumulation with a 20% cutoff value was accepted as positive staining. Of the 99 patients, 52 (53%) had histologically superficial bladder tumors, and 47 (47%) had invasive tumors. Data concerning grade, stage, number of recurrences, and disease progression were available for each patient. RESULTS: The median follow-up period was 55 months. 60 of the 99 patients (61%) had p53 overexpression. The difference for p53 overexpression between low-grade and high-grade tumors was significant (p < 0.05). In low- and high-grade tumors, there was no significant relationship for recurrence between p53-positive and p53-negative groups. But there was a statistically significant relationship between progression and histological grade of the tumors. p53 had no significant relationship with tumor recurrences (p > 0.05), but its relationship with progression was statistically significant (p < 0.05). CONCLUSIONS: We did not find a correlation between tumor recurrence and p53 overexpression, but p53 overexpression has a predictive value in determining tumor progression. High-grade tumors had higher p53-positive values than low-grade tumors. This group of patients should be considered for radical therapies on the basis of other prognostic parameters.     

The earliest thymic T cell progenitors sustain B cell and myeloid lineage potential

The stepwise commitment from hematopoietic stem cells in the bone marrow to T lymphocyte-restricted progenitors in the thymus represents a paradigm for understanding the requirement for distinct extrinsic cues during different stages of lineage restriction from multipotent to lineage-restricted progenitors. However, the commitment stage at which progenitors migrate from the bone marrow to the thymus remains unclear. Here we provide functional and molecular evidence at the single-cell level that the earliest progenitors in the neonatal thymus had combined granulocyte-monocyte, T lymphocyte and B lymphocyte lineage potential but not megakaryocyte-erythroid lineage potential. These potentials were identical to those of candidate thymus-seeding progenitors in the bone marrow, which were closely related at the molecular level. Our findings establish the distinct lineage-restriction stage at which the T cell lineage-commitment process transits from the bone marrow to the remote thymus.     

Stem Cell Therapy in Spinal Cord Injury: In Vivo and Postmortem Tracking of Bone Marrow Mononuclear or Mesenchymal Stem Cells

Objective

The aim of this study was to address the question of whether bone marrow-originated mononuclear cells (MNC) or mesenchymal stem cells (MSC) induce neural regeneration when implanted intraspinally.

Materials and Methods

The study design included 4 groups of mice: Group 1, non-traumatized control group; Groups 2, 3 and 4 spinal cord traumatized mice with 1 g force Tator clips, which received intralesionally either no cellular implants (Group 2), luciferase (Luc) (+) MNC (Group 3) or MSC (Group 4) obtained from CMV-Luc or beta-actin Luc donor transgenic mice. Following the surgery until decapitation, periodical radioluminescence imaging (RLI) and Basso Mouse Scale (BMS) evaluations was performed to monitor neural activity. Postmortem immunohistochemical techniques were used to analyze the fate of donor type implanted cells.

Results

All mice of Groups 3 and 4 showed various degrees of improvement in the BMS scores, whereas there was no change in Groups 1 and 2. The functional improvement was significantly better in Group 4 compared to Group 3 (18 vs 8, p?=?0.002). The immunohistochemical staining demonstrated GFP⁺Luc⁺ neuronal/glial cells that were also positive with one or more of these markers: nestin, myelin associated glycoprotein, microtubule associated protein or myelin oligodendrocyte specific protein, which is considered as indicator of donor type neuronal regeneration. Frequency of donor type neuronal cells; Luc + signals and median BMS scores were observed 48–64 % and 68–72 %; 44–80 %; 8 and 18 within Groups III and IV respectively.

Discussion

MSCs were more effective than MNC in obtaining neuronal recovery. Substantial but incomplete functional improvement was associated with donor type in vivo imaging signals more frequently than the number of neuronal cells expressing donor markers in spinal cord sections in vitro. Our results are in favor of functional recovery arising from both donor MSC and MNCs, contributing to direct neuronal regeneration and additional indirect mechanisms.     

Antibodies reactive to non-HLA antigens in transplant glomerulopathy

Although T and B cell alloimmunity contribute to transplant injury, autoimmunity directed at kidney-expressed, non-HLA antigens may also participate. Because the specificity, prevalence, and importance of antibodies to non-HLA antigens in late allograft injury are poorly characterized, we used a protein microarray to compare antibody repertoires in pre- and post-transplant sera from several cohorts of patients with and without transplant glomerulopathy. Transplantation routinely induced changes in antibody repertoires, but we did not identify any de novo non-HLA antibodies common to patients with transplant glomerulopathy. The screening studies identified three reactivities present before transplantation that persisted after transplant and strongly associated with transplant glomerulopathy. ELISA confirmed that reactivity against peroxisomal-trans-2-enoyl-coA-reductase strongly associated with the development of transplant glomerulopathy in independent validation sets. In addition to providing insight into effects of transplantation on non-HLA antibody repertoires, these results suggest that pretransplant serum antibodies to peroxisomal-trans-2-enoyl-coA-reductase may predict prognosis in kidney transplantation.     

Impaired systemic endothelial function in patients with pseudoexfoliation syndrome

Pseudoexfoliation syndrome (PEX) is the most common clinical precursor of open-angle glaucoma. Recent studies have shown that pseudoexfoliative material is widely distributed throughout the body, including blood vessels. The aim of our study was to evaluate endothelial function in the brachial artery of patients with pseudoexfoliation syndrome. We prospectively examined 23 patients with PEX (mean age, 70 +/- 8 years) and 20 healthy age- and sex-matched individuals (mean age, 68 +/- 9 years) as a control group. Brachial artery endothelial function was assessed by vascular response to reactive hyperemia (flow-mediated dilation (FMD) and sublingual nitroglycerin (NTG-mediated dilation) using high-resolution ultrasound. Flow-mediated and NTG-induced dilation were expressed as the percent change in diameter after reactive hyperemia and after NTG administration relative to the baseline value, respectively. Patients with cardiovascular disease and other conditions associated with endothelial dysfunction were excluded. When compared with controls, patients with PEX had significantly lower flow-mediated dilation (4.5 +/- 2.8 versus 8.2 +/- 3.7, P = 0.01) and NTG-mediated dilation (10.9 +/- 3.1 versus 15.8 +/- 3.8, P = 0.0001). Flow-mediated dilation and NTG-mediated dilation were similar in PEX patients with glaucoma (n = 11) and without glaucoma (n = 12). Flow-mediated and NTG-mediated dilation did not correlate with any measured parameter in any patient or control subject. The findings indicate that systemic endothelial function is impaired in PEX syndrome patients.