H. Rogier van den Berg,* Nisar A. Khan,† Marten van der Zee,† Fred Bonthuis,* Jan N. M. IJzermans,* Willem A. Dik,† Ron W. F. de Bruin,* and Robbert Benner†
*Department of Surgery, Laboratory for Experimental Surgery; and †Department of Immunology, Erasmus MC, Rotterdam, The Netherlands
Abstract:
Severe hemorrhagic shock (HS) followed by resuscitation induces a massive inflammatory response, which may culminate into systemic inflammatory response syndrome, multiple organ dysfunction syndrome, and, finally, death. Treatments that effectively prevent this inflammation are limited so far. In a previous study, we demonstrated that synthetic oligopeptides related to the primary structure of human chorionic gonadotropin (HCG) can inhibit the inflammatory response and mortality that follow high-dose LPS-induced inflammation. Considering this powerful antiinflammatory effect, we investigated whether administration of similar synthetic HCG-related oligopeptides (LQGV, AQGV, LAGV) during HS were able to attenuate the inflammatory response associated with this condition. Hemorrhagic shock was induced in rats for 60 min by blood withdrawal until a MAP of 40 mmHg was reached. Rats received a single injection with one of the hCG-related oligopeptides (LQGV, AQGV or LAGV) or 0.9% NaCl solution as control 30 min after induction of HS. Treatment with LQGV, AQGV, or LAGV prevented systemic release of TNF-α and IL-6 and was associated with reduced TNF-α, IL-6, and E-selectin mRNA transcript levels in the liver. LQGV treatment prevented neutrophil infiltration into the liver and was associated with reduced liver damage. Our data suggest that HCG-related oligopeptides, in particular LQGV, have therapeutic potential by attenuating the life-threatening inflammation and organ damage that is associated with (trauma) HS and resuscitation.
Dissection of Systems, Cell Populations and Molecules
R. Benner & N. A. Khan
Department of Immunology, Erasmus MC – University Medical Center Rotterdam, Rotterdam, The Netherlands
Abstract:
This paper summarizes studies on antibody formation in the bone marrow and the suppressive effects of intravenous immunization with allogeneic blood cells on T-cell function in mice. The latter studies were extended by employing the limiting dilution culture system developed in Ivan Lefkovits’ laboratory and implemented in collaboration with Lucien Aarden. Thereby, the functional data were complemented with frequencies of alloantigen-activated helper (Th) and suppressor T cells after intravenous alloimmunization. These results led the Rotterdam group to studies on the prevention of rejection of the foetal ‘allograft’. Th cells are central in foetal allograft rejection and pregnancy success. Characteristic for human pregnancy is the production of the glycoprotein chorionic gonadotropin (hCG) hormone. The in vivo liberated peptide fragments originating from nicking of the sequence MTRVLQGVLPALPQ in the β-chain of hCG were considered for their immunoregulating capacity related to pregnancy success. These peptides – prepared synthetically – (MTR, MTRV, LQG, LQGV, VLPALP and others) indeed showed a remarkable spectrum of biological effects (e.g. modulation of angiogenesis, inhibition of septic shock syndrome, prevention of diabetes and reduction of ischaemia-reperfusion damage). The paper interprets and generalizes these findings and projects them into various research directions, especially towards the proteomics framework studies built up in Ivan Lefkovits’ laboratory in the nineties. During the time period, when Ivan spent a mini-sabbatical in Rotterdam (months after closing down the BII) more detailed discussions were intiated. This paper is meant to keep the discussions between the involved research groups going on.
Nisar A. Khan, Afshan Khan, Huub F. J. Savelkoul, and Robbert Benner
Department of Immunology, Erasmus University and University Hospital Rotterdam
Abstract:
Human chorionic gonadotrophin (hCG) is a heterodimeric placental glycoprotein hormone required in pregnancy. In human pregnancy urine and in commercial hCG preparations (c-hCG) it occurs in a variety of forms, including breakdown products. Several reports have suggested modulation of the immune system by intact hormone, but such effects of breakdown products have not been reported. In a related article (Hum Immunol 62:1315, 2001), it is reported that a 400–2000 Dalton (Da) fraction from c-hCG and from human pregnancy urine inhibits Th1-mediated diabetes in NOD mice. The active component(s) were called natural (immuno) modulatory pregnancy factor(s) (NMPF). This study reports that a single treatment with the same low molecular weight NMPF fraction up to 24-h after high dose lipopolysaccharide (LPS) injection inhibited septic shock in mice. This counteracting effect of NMPF paralleled the downregulation of the effects of LPS on the production of macrophage migration inhibitory factor (MIF) by spleen cells, on the plasma level of liver aminotransferase, and on the expression of several splenic lymphocyte and macrophage surface markers. Based on the primary structure of the ß-chain of hCG a synthetic hexapeptide Valine-Leucin-Proline-Alanine-Leucine-Proline (VLPALP) was designed, which demonstrated it to have the same protective effects as the 400–2000 Da NMPF fraction. These results indicate a new strategy for the treatment of septic shock and the potential of therapeutic use of this synthetic oligopeptide.
Inhibition of Diabetes in NOD Mice by Human Pregnancy Factor
Nisar A. Khan, Afshan Khan, Huub F. J. Savelkoul, and Robbert Benner
Department of Immunology, Erasmus University and University Hospital Rotterdam
Abstract:
Clinical symptoms of Th1 mediated autoimmune diseases regress in many patients during pregnancy. A prominent feature of pregnancy is the presence of human chorionic gonadotrophin hormone (hCG) in blood and urine. In this report we tested the effect of clinical grade hCG (c-hCG) on the development of diabetes, a Th1 mediated autoimmune disease, in nonobese diabetic (NOD) mice. We show that treatment of NOD mice with c-hCG before the onset of clinical symptoms lowered the increased blood glucose levels, reversed the established inflammatory infiltrate of pancreatic tissue, and profoundly inhibited the development of diabetes for prolonged time. c-hCG also induced profound inhibition of the functional activity (i.e. production of IFN-γ) of Th1 cells. Transfer of spleen cells from c-hCG-treated NOD mice into immunocompromised NOD.SCID mice inhibited the development of diabetes in these otherwise nontreated mice. This shows that the treatment of the donor NOD mice induced persistent changes in the immune system. The antidiabetic activity of c-hCG was not caused by heterodimeric hCG or its subunits. Instead, this antidiabetic activity resided in a fraction of c-hCG preparation that contains a 400–2000 Dalton natural (immuno) modulatory pregnancy factor (NMPF).