Prevention of autoimmune diabetes with nonactivating anti-CD3 monoclonal antibody.

Autoreactive T cells mediate diabetes in animal models of insulin-dependent diabetes mellitus (IDDM) and are believed to cause the disease in humans. Therefore, immunotherapies directed against T cells are of particular interest for the treatment of IDDM. One candidate for such immunotherapy is anti-CD3 monoclonal antibodies (MoAbs), but clinical side effects are common with anti-CD3 treatment due to the ability of these MoAbs to activate T cells in vivo. However, F(ab')2 fragments of anti-CD3 are nonactivating and immunosuppressive. We evaluated the effects of whole anti-CD3 MoAb and F(ab')2 fragments in the setting of experimental autoimmune diabetes. Treatment with whole MoAb or F(ab')2 fragments significantly reduced the hyperglycemia induced with multiple low dosages of streptozocin (MDSDM; 232 +/- 23 mg/dl, P less than 0.01 and 235 +/- 16 mg/dl, P less than 0.01 vs. 325 +/- 25 mg/dl, respectively) in male CD1 mice. Both whole MoAb and F(ab')2 fragments suppressed the development of insulitis (P less than 0.001). Treatment with whole MoAb resulted in marked weight loss (10.4 +/- 1.5% of total body wt), and the mice appeared ill and listless, whereas, mice treated with F(ab')2 fragments gained weight (4.9 +/- 5.5% of total body wt) and appeared healthy. Treatment with whole MoAb caused activation of T cells in vivo as reflected by proliferation of freshly isolated spleen cells to recombinant interleukin-2. Depletion of T cells with whole MoAb was more pronounced than with F(ab')2 fragments, and T-cell receptor (TCR) reexpression on remaining cells occurred with F(ab')2 fragments within 48 h after F(ab')2 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of medium- and long-chain triglycerides on sleep and thermoregulatory processes in neonates

Sleep processes and body temperature regulation of neonates are never taken into account in the evaluation of nutrients, although these functions are implicated in the regulation of energy metabolism and are influenced by the nutritional state and its metabolic consequences. Medium-chain triglycerides (MCT) are currently used in paediatric units during the first weeks of because they are considered to be a rapid source of energy, easy to assimilate for growing premature infants, whose digestive function is immature. However, no study has described the thermic effect of these nutrients on body temperature regulation and sleep. The present study aimed at analysing the influence of three feeding formulas with different content of MCT on sleep processes and on thermoregulation of neonates fed until desired intake was reached. Whatever the thermal conditions (thermal equilibrium or cool environment), the MCT-fed groups had higher body temperatures and than groups fed without MCT, for whom total sleep time was reduced at thermal equilibrium. In this group, the large amount of quiet sleep seems to favour a strategy of conserving energy . Higher energy expenditure in MCT-fed groups is not harmful to growth rate since nutritional efficiency is even better reflected by a larger body mass gain. The thermic effect of MCT contributes to lessening the vulnerability of neonates exposed to low incubator temperatures.     

Maximizing CD8+ T cell responses elicited by peptide vaccines containing CpG oligodeoxynucleotides

We assessed the ability of several factors to increase the size of tumor-antigen-specific CD8(+) T cell responses elicited by vaccines incorporating peptides and CpG-containing oligodeoxynucleotides (CpG). Neither granulocyte-macrophage colony-stimulating factor (GM-CSF) nor an immunogenic MHC class II-presented "helper" peptide increased the size of epitope-specific CD8+ T cell responses elicited by peptide+CpG-containing vaccines. In contrast, low-dose subcutaneous interleukin (IL)-2 dramatically increased the size of splenic and peripheral blood epitope-specific CD8(+) T cell responses generated by peptide+CpG-containing vaccines. Moreover, peptide+CpG-containing vaccines plus low-dose IL-2 mediated anti-tumor immunity. A prime-boost vaccination schedule elicited larger CD8(+) T cell responses than a weekly vaccination schedule. Including larger doses of peptide in vaccines led to larger vaccine-elicited CD8(+) T cell responses. Clinical trials of CpG-containing peptide vaccines are ongoing. These findings suggest strategies to increase the size of CD8(+) T cell responses generated by CpG-containing peptide vaccines that could be tested in future clinical trials.     

Clonal deletion of postthymic T cells: veto cells kill precursor cytotoxic T lymphocytes

Veto cell-mediated suppression of cytotoxic T lymphocyte (CTL) responses has been proposed as one mechanism by which self-tolerance is maintained in mature T cell populations. We have previously reported that murine bone marrow cells cultured in the presence of high-dose interleukin 2 (IL-2) (activated bone marrow cells [ABM]) mediate strong veto suppressor function. To examine mechanisms by which ABM may suppress precursor CTL (p-CTL) responses, we used p-CTL generated from spleen cells of transgenic mice expressing a T cell receptor specific for H-2 Ld. It was demonstrated that the cytotoxic response by these p-CTL after stimulation with irradiated H-2d/k spleen cells was suppressed by DBA/2 (H-2d) ABM, but not by B10.BR (H-2k) ABM or dm1 (Dd, Ld mutant) ABM. Flow cytometry analysis with propidium iodide staining revealed that these p-CTL were specifically deleted by incubation with H-2d ABM, but not with H-2k ABM. These data indicate that ABM veto cells kill p-CTL with specificity for antigens expressed on the surface of the ABM, and that the mechanism for veto cell activity of ABM is clonal deletion of p-CTL.     

Regrowth of the rat biliary tree after 70% partial hepatectomy is coupled to increased secretin-induced ductal secretion

BACKGROUND & AIMS: After partial hepatectomy, liver regeneration occurs with the return of hepatocyte mass to normal, Limited data exist regarding the renewal of the biliary tree after partial hepatectomy. This study tested the hypothesis that, after partial hepatectomy, the biliary tree regenerates by proliferation of the remaining cholangiocytes, leading to an increase in secretin-induced ductal bile secretion. METHODS: After 70% partial hepatectomy, cholangiocyte proliferation was assessed in situ by morphometric analysis and In vitro by measurement of 3H-thymidine incorporation. Ductal secretion was estimated by measurement of secretin receptor gene expression and adenosine 3',5'-cyclic monophosphate (cAMP) levels in vitro and by the effect of secretin on ductal bile secretion in vivo. RESULTS: DNA synthesis was undetectable in control cholangiocytes, increased and peaked at day 3 after partial hepatectomy, and returned to normal by day 28. Morphometric analysis showed regrowth of the biliary tree beginning at day 1 with restoration by day 10. The expression of secretin receptor gene and secretin-induced cAMP levels and secretin- induced bicarbonate-rich choleresis increased during the period of bile duct renewal. CONCLUSIONS: After partial hepatectomy, the increase in secretin-induced ductal bile secretion observed during bile duct renewal results from proliferation of remaining cholangiocytes. (Gastroenterology 1996 Dec;111(6):1633-44)