IL-2 Pathway Blocking in Combination with Anti-CD154 Synergistically Establishes Mixed Macrochimerism with Limited Dose of Bone Marrow Cells and Prolongs Skin Graft Survival in Mice

To facilitate the establishment of mixed chimerism with limited dose of bone marrow (BM) cells, and to achieve tolerance in skin graft model, combined blocking of costimulatory pathway and IL-2 pathway was used in minimally myeloablative model using busulfan. BM cells (2.5×107) of BALB/c were injected into C57BL/6 mice at day 0 with full thickness skin graft after single dose injection of busulfan (25 mg/kg) on day -1. Recipients were grouped and injected the anti-CD154, CTLA4-Ig, anti-IL-2R at days 0, 2, 4, and 6 according to protocol. Mixed macrochimerism were induced in groups treated with anti-CD154+anti-CTLA4-Ig, anti-CD154+anti-IL-2R, and anti-CD154+anti-CTLA4 Ig+anti-IL-2R. Three groups having chimerism enjoyed prolonged graft survival more than 6 months. Superantigen deletion study revealed deletion of alloreactive T cells in combined blockade treated groups. In graft versus host disease model using CFSE staining, CD4+ T cell and CD8+ T cell proliferation were reduced in groups treated with CTLA4-Ig or anti-IL-2R or both in combination with anti-CD154. However, anti-IL-2R was not so strong as CTLA4-Ig in terms of inhibition of T cell proliferation. In conclusion, IL-2 pathway blocking combined with anti-CD154 can establish macrochimerism with limited dose of BM transplantation and induce specific tolerance to allograft

Evaluation of the 7th AJCC TNM Staging System in Point of Lymph Node Classification

Purpose: The 7th AJCC tumor node metastasis (TNM) staging system modified the classification of the lymph node metastasis widely compared to the 6th edition. To evaluate the prognostic predictability of the new TNM staging system, we analyzed the survival rate of the gastric cancer patients assessed by the 7th staging system. Materials and Methods: Among 2,083 patients who underwent resection for gastric cancer at the department of surgery, Hanyang Medical Center from July 1992 to December 2009, This study retrospectively reviewed 5-year survival rate (5YSR) of 624 patients (TanyN3M0: 464 patients, TanyNanyM1: 160 patients) focusing on the number of metastatic lymph node and distant metastasis. We evaluated the applicability of the new staging system. Results: There were no significant differences in 5YSR between stage IIIC with more than 29 metastatic lymph nodes and stage IV (P=0.053). No significant differences were observed between stage IIIB with more than 28 metastatic lymph nodes and stage IV (P=0.093). Distinct survival differences were present between patients who were categorized as TanyN3M0 with 7 to 32 metastatic lymph nodes and stage IV. But patients with more than 33 metastatic lymph nodes did not show any significant differences compared to stage IV (P=0.055). Among patients with TanyN3M0, statistical significances were seen between patients with 7 to 30 metastatic lymph nodes and those with more than 31 metastatic lymph nodes. Conclusions: In the new staging system, modifications of N classification is mandatory to improve prognostic prediction. Further study involving a greater number of cases is required to demonstrate the most appropriate cutoffs for N classification. ??? 2011 by The Korean Gastric Cancer Association

Diagnostic criteria for diabetes revisited: making use of combined criteria

BACKGROUND: Existing cut-offs for fasting plasma glucose (FPG) and post-load glucose (2hPG) criteria are not equivalent in the diagnosis of diabetes and glucose intolerance. Adjusting cut-offs of single measurements have not helped so we undertook this project to see if they could be complementary. METHODS: We performed oral glucose tolerance tests and mean levels of hemoglobin A1c (HbA1c) measurements on 43 patients referred to a diabetes clinic for possible diabetes. Results of single and combined use of the FPG and 2hPG criteria were evaluated against the levels of HbA1c and results re-interpreted in the light of existing reports in the literature. RESULTS: Our results confirm that the FPG and the 2hPG, being specific and sensitive respectively for the presence of glucose intolerance or diabetes, are not equivalent. They are shown to be indeed complementary and a re-definition of diagnostic criteria based on their combined use is proposed. CONCLUSIONS: We conclude that altering single measurement cut-offs for the diagnosis of diabetes and altered glucose tolerance will not result in better outcomes. We present the case for a combined criteria in the diagnosis and definition of diabetes with a FPG≥7 mmol/L AND 2-hour glucose ≥7.8 mmol/L being used to define diabetes while a FPG<7 mmol/L AND 2-hour glucose <7.8 mmol/L being used to define normality. Discordant values will define impaired glucose tolerance (IGT). This proposal requires prospective evaluation in a large cohort

Disease recurrence in paediatric renal transplantation

Renal transplantation (Tx) is the treatment of choice for end-stage renal disease. The incidence of acute rejection after renal Tx has decreased because of improving early immunosuppression, but the risk of disease recurrence (DR) is becoming relatively high, with a greater prevalence in children than in adults, thereby increasing patient morbidity, graft loss (GL) and, sometimes, mortality rate. The current overall graft loss to DR is 7–8%, mainly due to primary glomerulonephritis (70–80%) and inherited metabolic diseases. The more typical presentation is a recurrence of the full disease, either with a high risk of GL (focal and segmental glomerulosclerosis 14–50% DR, 40–60% GL; atypical haemolytic uraemic syndrome 20–80% DR, 10–83% GL; membranoproliferative glomerulonephritis 30–100% DR, 17–61% GL; membranous nephropathy ∼30% DR, ∼50% GL; lipoprotein glomerulopathy ∼100% DR and GL; primary hyperoxaluria type 1 80–100% DR and GL) or with a low risk of GL [immunoglobulin (Ig)A nephropathy 36–60% DR, 7–10% GL; systemic lupus erythematosus 0–30% DR, 0–5% GL; anti-neutrophilic cytoplasmic antibody (ANCA)-associated glomerulonephritis]. Recurrence may also occur with a delayed risk of GL, such as insulin-dependent diabetes mellitus, sickle cell disease, endemic nephropathy, and sarcoidosis. In other primary diseases, the post-Tx course may be complicated by specific events that are different from overt recurrence: proteinuria or cancer in some genetic forms of nephrotic syndrome, anti-glomerular basement membrane antibodies-associated glomerulonephritis (Alport syndrome, Goodpasture syndrome), and graft involvement as a consequence of lower urinary tract abnormality or human immunodeficiency virus (HIV) nephropathy. Some other post-Tx conditions may mimic recurrence, such as de novo membranous glomerulonephritis, IgA nephropathy, microangiopathy, or isolated specific deposits (cystinosis, Fabry disease). Adequate strategies should therefore be added to kidney Tx, such as donor selection, associated liver Tx, plasmatherapy, specific immunosuppression protocols. In such conditions, very few patients may be excluded from kidney Tx only because of a major risk of DR and repeated GL. In the near future the issue of DR after kidney Tx may benefit from alternatives to organ Tx, such as recombinant proteins, specific monoclonal antibodies, cell/gene therapy, and chaperone molecules

Costimulation and autoimmune diabetes in BB rats

Costimulatory signals regulate T-cell activation. To investigate the role of costimulation in autoimmunity and transplantation, we studied the BB rat model of type 1 diabetes. Diabetes-prone BB (BBDP) rats spontaneously develop disease when 55-120 days of age. We observed that two anti-CD28 monoclonal antibodies (mAb) with different functional activities completely prevented diabetes in BBDP rats. Anti-CD154 mAb delayed diabetes, whereas treatment with CTLA4-Ig or anti-CD80 mAb accelerated disease. Anti-CD86 or anti-CD134L mAbs had no effect. Diabetes resistant BB (BBDR) rats are disease-free, but > 95% of them develop diabetes after treatment with polyinosinicpolycytidylic acid and an mAb that depletes Treg cells. In the induced BBDR model, anti-CD154 mAb delayed onset of diabetes, whereas CTLA4-Ig, anti-CD134L or either of the anti-CD28 mAbs had little or no effect. In contrast, blockade of the CD134-CD134L pathwa