Inhibitory effects of AcSDKP on the mixed lymphocyte reaction (MLR). Part I. MLR with mouse spleen cells.

AcSDKP (inhibitor of entry into cycle of pluripotent hemopoietic stem cells) is able to decrease mixed lymphocyte reaction intensity when H-2 incompatible allogeneic spleen cells are used as stimulators. This is a first approach to determining whether AcSDKP has potential therapeutic value for clinical bone marrow transplantation.

Inhibitory effects of AcSDKP on the mixed lymphocyte reaction (MLR). Part II. Human whole blood cells.

AcSDKP is a physiological negative regulator of hematopoietic stem cell proliferation. To investigate the applicability of AcSDKP in the prevention of graft-versus-host disease, this tetrapeptide was tested in mice and showed an inhibitory effect on the mixed lymphocyte reaction (MLR). In this paper we report MLR using human whole blood cells. The maximum inhibitory effect (50%) was obtained at 2.5 ng/ml AcSDKP. All experiments showed a constant dose response. Experiments are now being conducted to elucidate the mechanism of this inhibition.

Correlation of endogenous acetyl-ser-asp-lys-pro plasma levels in mice and the kinetics of pluripotent hemopoietic stem cells entry into the cycle after cytosine arabinoside treatment: fundamental and clinical aspects.

A decrease of endogenous acetyl-ser-asp-lys-pro (AcSDKP) levels in murine plasma was observed after Ara-C treatment. This decrease preceded the entry of pluripotent hemopoietic stem cells (CFU-S) into the cell cycle. This suggests a correlation between CFU-S kinetics and levels of endogenous AcSDKP. The subsequent increase of AcSDKP levels seem to indicate a feedback mechanism which should permit the reestablishment of homeostasis in the stem cells. Therefore, the expulsion of the physiological brake may be the response to a signal (stimulatory factors) to start dividing and the retention of the physiological brake may the mechanism for a return to normal values of cell proliferation.

Production and consumption of the tetrapeptide AcSDKP, a negative regulator of hematopoietic stem cells, by hematopoietic microenvironmental cells.

This study was performed to evaluate the role of human microenvironmental cells in the metabolism of AcSDKP, a physiological inhibitor of hematopoietic stem cells. Using long-term marrow cultures (LTMCs), whose medium already contained a baseline value of AcSDKP, we found after 2 weeks a net output in the culture supernatant indicating that release by cells from the adherent layer was superior to consumption of the peptide. Since human microenvironmental cells consist of macrophages and vascular smooth-muscle-like stromal cells we generated pure populations of macrophages (by culturing cord blood cells in the presence of granulomonocytic colony-stimulating factor) and of stromal cells (generated by stromal colonies). We found in supernatants of macrophage cultures a significantly (p < 0.01) increased level of AcSDKP (compared with value in medium) while in supernatants of stromal cell cultures the level was decreased. Cell content of angiotensin-converting enzyme (ACE) in stromal cells was higher than in macrophages, which suggests a degradation of AcSDKP by stromal cells because of their higher amount of ACE. Finally, we analyzed the content of AcSDKP in adherent layers of LTMCs (with or without extracellular matrix [ECM] components), macrophages, and stromal cells. We found levels of AcSDKP of 1.5 pMol per 106 cells in extracts from macrophages or from stromal cells. On the contrary, extracts from primary layers of LTMCs contained 3 times more AcSDKP; however, after treatment of primary layers by collagenase, AcSDKP level fell to 1 pMol per 10(6) cells. Immunofluorescence using an anti-AcSDKP monoclonal antibody showed an extracellular network in certain areas of LTMCs. This study shows that 1) macrophages synthesize and release in the supernatant AcSDKP, 2) stromal cells probably degrade the peptide via ACE, and 3) components of the ECM from LTMCs serve as a reservoir for the peptide. These results are reminiscent of what has been described for growth factors, produced by microenvironmental cells, and stored in the ECM in close vicinity to hematopoietic precursors.

AcSDKP plasma concentrations in patients with solid tumours: comparison of two chemotherapeutic regimens.

The tetrapeptide AcSer-Asp-Lys-Pro (AcSDKP) is a physiological inhibitor of the proliferation of haematopoietic stem cells and progenitors. In Ara-C-treated mice, its plasmatic concentrations decrease while the CFU-S start cycling. Infusion of synthetic AcSDKP (Goralatide) at this time protects them from haematoxicity by blocking early cycling of CFU-S. Both in vitro and in vivo, this effect seems to be optimal in a narrow range of concentrations. Thus, a better knowledge of the kinetics of endogenous AcSDKP during cancer treatment could help to optimize the treatments with Goralatide. AcSDKP plasma levels have been measured by a specific EIA in 14 cancer patients during the two initial monthly 5 day courses of chemotherapy with 5-FU alone administered either by continuous infusions (six patients) or by 1 h daily infusions (eight patients). AcSDKP concentrations did not vary significantly during the first and the second course. Together with our previous results in AML patients treated with high doses chemotherapy (Ara-C and Anthracyclin), our present data suggest that the variations of endogenous AcSDKP in patients are dependent of the type, doses and schedule of chemotherapy.

[A method for evaluating the safety of decompression regimens for divers]. / Sposob otsenki bezopasnosti rezhimov dekompressii vodolazov.

The authors offer a way of estimation of safety modes of decompression, based on definition of intensity of venous gas embolism (VGE) at each decompression and account of probability of illness of divers in series of tests. Intensity of VGE was determined with the help of ultrasonic gas bubbles Doppler radar. Comparative safety of standard modes of decompression of divers of the Navy was estimated, and also the modes, designed in accordance with mathematical model of decompression, offered by I. A. Voitsekhovich (1990), were done. The results testify, that use of ultrasonic radar for estimation of intensity of VGE at decompression and account of average and maximum probability of decompression illness in series of tests of modes permit to receive the comparative characteristic of safety of modes at small number of decompressions.

[Human resistance to decompression sickness and nonspecific methods of its elevation]. / Ustoichivost' liudei k dekompressionnoi bolezni i nespetsificheskie metody ee povysheniia.

The object of this study was the dependence of decompression sickness (DCS) tolerance determined by the intensity of venous gas embolism on functioning of the cardiovascular and respiratory systems, and micro-circulation which predetermine wash-out of an indifferent gas. Efficiency of nonspecific methods, e.g. hypercapnic training, hyperbaric oxygenation, exposures to pulse current to enhance human tolerance to DCS was experimentally substantiated.

[Study of the role of negative regulator, AcSer-Asp-Lys-Pro (AcSDKP) in the phenomena of cellular proliferation]. / L'étude du rôle d'un régulateur négatif, l'AcSer-Asp-Lys-Pro (AcSDKP) dans les phénomènes de prolifération cellulaire.

The intra and extracellular kinetics of AcSDKP levels in cell culture have been studied. A close correlation was observed between the minimal level of intracellular AcSDKP (a negative regulator of cell proliferation) and the initiation of DNA synthesis. The return to initial levels of intracellular AcSDKP when the rate of DNA synthesis decreases, suggests a role for the tetrapeptide in homeostasis during cell growth. The return to normal values was not observed in preliminary studies on cell lineages during uncontrolled proliferation.