Subject(s)
Receptors, Histamine H1/metabolism , Signal Transduction/physiology , Adenylyl Cyclases/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , Cyclic AMP/metabolism , Histamine/chemistry , Histamine/metabolism , Humans , Inositol Phosphates/metabolism , Ligands , Models, Molecular , Protein Conformation , Receptors, Histamine H1/chemistry , Receptors, Histamine H1/genetics , Type C Phospholipases/metabolismABSTRACT
A bridged peptide with the sequence: H-Thr-Pro-Gln-Arg-Gly-Asp-Val-gamma-Abu-Asn-Asp-Gln-Glu-Glu-Thr-Thr-Gly-Val-Val-Ser-Thr-Pro-Leu-Ile-Arg-Asn-Gly-OH was designed to mimic the discontinuous epitope of the HLA-DQ molecule that might interact with CD4. The bridged peptide revealed distinct suppressory effect in the humoral immune response. This result supports our suggestion that the 164-172 region of the HLA-DQ molecule may enhance its interactions with coreceptors, possibly with CD4.
Subject(s)
Immunosuppressive Agents/chemistry , Immunosuppressive Agents/chemical synthesis , Immunosuppressive Agents/pharmacology , Peptides/chemistry , Animals , Binding Sites , CD4 Antigens/biosynthesis , CD4 Antigens/chemistry , Epitopes , HLA-DQ Antigens/chemistry , Humans , Mice , Models, Molecular , Peptides/chemical synthesis , Protein Structure, Tertiary , Time FactorsABSTRACT
Our previous studies revealed that the nonapeptide fragment of HLA-DQ located in the beta 164-172 loop of the Thr-Pro-Gln-Arg-Gly-Asp-Val-Tyr-Thr sequence suppresses the immune humoral and cellular responses [30]. Based on the crystal structure of HLA-class II molecules we designed and synthesized a cyclic analog with restricted conformation, cyclo(Suc-Thr-Pro-Gln-Arg-Gly-Asp-Val-Lys)-Thr-OH (Suc = succinyl) by reacting a Lys side chain with a succinylated N-terminus. The cyclization product more potently suppresses the cellular immune response than its linear counterparts and is efficiently cleaved by trypsin. The results indicate that the beta 164-172 loop may serve as a functional epitope on the HLA class II surface for intermolecular binding.
Subject(s)
HLA-DQ Antigens/chemistry , HLA-DQ Antigens/immunology , Peptides/chemistry , Amino Acid Sequence , Amino Acids/chemistry , Animals , Chromatography, High Pressure Liquid , Circular Dichroism , Crystallography, X-Ray , Dose-Response Relationship, Drug , Epitopes , Hypersensitivity , Mice , Models, Chemical , Molecular Sequence Data , Peptide Biosynthesis , Protein Binding , Protein Conformation , Protein Structure, Tertiary , Spleen/cytology , Thymopentin/chemistry , Time FactorsABSTRACT
Our previous studies showed, that the,TPQRGDVYT, QRGDVYT and RGDVYT fragments, located in the beta164-172 loop of HLA-DQ, strongly suppress the humoral and cellular immune response, while their shorter analogs, RGDV, RGDVY, and QRGDVY, show only weak stimulatory activity in respect to humoral immunological response. The fragments contain the RGDVY sequence that is analogous to thymopentin (pentapeptide RKDVY, an immune system activator) as well as the RGD sequence, known for its importance for cellular association phenomena. Based on the crystal structure of HLA-DR1, we also designed and synthesized a cyclic analog C*RGDVYC* (where C* indicates Cys participating in disulfide bridge) with restricted conformation, which strongly suppresses both humoral and cellular immune response. In the present study we synthesized and tested the immunological properties of the linear and cyclic HLA-DP and HLA-DR counterparts of all the above HLA-DQ fragments. Although the results show that the linear HLA-DP fragments possess moderate immunosuppressory potency, their conformationally restricted analog, C*QGDVYC*C shows a considerable suppression of both humoral and cellular immune response. The nonapeptide fragment of HLA-DR, VPRSGEVYT and particularly its cyclic analog C*SGEVYC*, are strong suppressors of the humoral response.
Subject(s)
HLA-DP Antigens/chemistry , HLA-DR Antigens/chemistry , Immune Tolerance , Amino Acid Sequence , Animals , Antibody Formation , Circular Dichroism , HLA-DP Antigens/genetics , HLA-DR Antigens/genetics , Hemolytic Plaque Technique , Humans , Immunity, Cellular , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/immunology , Immunosuppressive Agents/pharmacology , Mice , Mice, Inbred CBA , Peptide Fragments/chemistry , Peptide Fragments/immunology , Peptide Fragments/pharmacology , Protein ConformationABSTRACT
Recently we showed that the fragments of HLA-DQ with the Thr-Pro-Gln-Arg-Gly-Asp-Val-Tyr-Thr and Gln-Arg-Gly-Asp-Val-Tyr-Thr sequences strongly suppress the immune response, while their shorter analogs, Arg-Gly-Asp-Val, Arg-Gly-Asp-Val-Tyr and Gln-Arg-Gly-Asp-Val-Tyr, show very weak stimulatory activity with respect to humoral immunological response. The fragments contain the sequence which is very similar to thymopentin (pentapeptide Arg-Lys-Asp-Val-Tyr, an active fragment (32-36) of thymopoietin, an immune system activator produced in thymi), and at the same time contains the Arg-Gly-Asp (RGD) sequence, known as an inhibitor of adhesion processes. In the present study we found that a hexapeptide: Arg-Gly-Asp-Val-Tyr-Thr is the smallest size fragment of HLA-DQ having both cellular and humoral immunosuppressive activity. We also found that linear and cyclic fragments of HLA-DQ do not affect cell line production of various cytokines, what suggests that the mechanism of interactions of these peptides with the immunological system is different as compared with most other known immunosuppressors.
Subject(s)
HLA-DQ Antigens/pharmacology , Immunosuppressive Agents/pharmacology , Peptide Fragments/pharmacology , Thymopentin/analogs & derivatives , Animals , Cell Line , Cytokines/analysis , Cytokines/biosynthesis , Cytokines/immunology , HLA-DQ Antigens/immunology , Humans , Mice , Mice, Inbred CBA , Peptides, Cyclic/pharmacology , Thymopentin/immunologyABSTRACT
Our previous studies showed that the nonapeptide fragment of human leukocyte antigen DQ with the TPQRGDVYT sequence strongly suppresses the immune response [Z. Szewczuk, I. Z. Siemion, and Z. Wieczorek (1996) Molecular Immunology, 33, 903-9081]. The fragment contains the RGDVY sequence, which is very similar to thymopentin (pentapeptide RKDVY, an active fragment (32-36) of thymopoietin, an immune system activator produced in thymi), and at the same time contains the RGD sequence, known as an inhibitor of adhesion processes. In the present study we tested an influence of the nonapeptide and its shorter fragments on binding the activated platelets and K562 cells to fibrinogen and fibronectin, respectively. We also designed and synthesized a cyclic thymopentin-like peptide. C*RGDVYC* (where C* indicates Cys participating in disulfide bridge) to restrict its conformation. The cyclization product strongly suppresses the humoral and cellular immune response and selectively inhibits the adhesion of K562 cells to fibronectin. The results are discussed in the light of CD conformational studies.
Subject(s)
Cell Adhesion/drug effects , HLA-DQ Antigens/chemistry , Immunosuppressive Agents/pharmacology , Peptide Fragments/pharmacology , Peptides, Cyclic/pharmacology , Platelet Adhesiveness/drug effects , Animals , Binding Sites , Blood Platelets/drug effects , Blood Platelets/metabolism , Circular Dichroism , Hemolytic Plaque Technique , Humans , Hypersensitivity, Delayed/immunology , Immunosuppressive Agents/chemical synthesis , Immunosuppressive Agents/chemistry , Mice , Models, Molecular , Peptide Fragments/chemical synthesis , Peptide Fragments/chemistry , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/chemistry , Protein Conformation , Tumor Cells, CulturedABSTRACT
This paper examines the incidence of child homicide in England and Wales, drawing on a review of files from the Director of Public Prosecutions in London from 1983 and 1984. After outlining the official statistics on child homicide, five factors are discussed which suggest that many cases of child-killing may be wrongly categorised. These factors are: cases where maltreatment is not the immediate cause of death, 'cot deaths', the legal difficulties of proof, cases where no body is found or identified and professional reluctance to act. Attempts to estimate the true incidence of child homicide are reviewed and the estimate calculated in the present study outlined.
ABSTRACT
The animal blood preparation Livex obtained from the Agricultural Academy in Wroclaw was used for treatment of anaemia of pregnancy. During four weeks of treatment (3 x 7.0 g of Livex added to diet) a statistically significant increase was found of anaemia parameters such as haemoglobin level, value of haematocrit, red blood cell count, and mean corpuscular volume. Other parameters such as mean corpuscular haemoglobin mass, and mean corpuscular haemoglobin concentration were also increased but statistically insignificantly. Livex is an effective and safe preparation causing no side effects in view of the presence of certain trace elements in it, especially iron, copper, zinc, cobalt, and selenium. The use of this preparation in the treatment of anaemia of pregnancy is a natural and effective method of erythropoietic process stimulation.
Subject(s)
Anemia/diet therapy , Biological Products/therapeutic use , Blood Proteins/therapeutic use , Dietary Proteins/therapeutic use , Pregnancy Complications, Hematologic/diet therapy , Animals , Erythropoiesis/physiology , Female , Humans , Pregnancy , Treatment OutcomeABSTRACT
Dependence of birth weight on insulin dosage in pregnant diabetic women, diabetes mellitus class (according to White) have been discussed. An analysis included 56 pregnancies complicated with diabetes mellitus, which were terminated at the I Department of Obstetrics, Medical Academy in Wroclaw between January, 1981 and January, 1988. Neonates birth weight is reversely proportional to insulin daily dose given to pregnant women diabetes mellitus during the III trimester of pregnancy. Diabetic angiopathy and nephropathy could be considered as factors deciding on the low birth weight of neonates delivered by the diabetic mothers despite euglycemia.
Subject(s)
Infant, Low Birth Weight , Insulin/administration & dosage , Pregnancy in Diabetics/drug therapy , Prenatal Exposure Delayed Effects , Female , Humans , Infant, Newborn , Pregnancy , Pregnancy Trimester, ThirdABSTRACT
The authors, basing in the survey of literature and on own experience, discuss pregnancy in diabetic patients together with possible complications. Pregnancy exerts an unfavourable effect on diabetes mellitus with significant vascular disorders being in some cases even life-threatening. An of clinical status of the diabetes mellitus should be always carefully assessed in every diabetic woman to avoid serious complications, which may occur later-during possible pregnancy. Date of pregnancy termination in every pregnant diabetic with vascular disorders should depend on not only on status of fetus but also of the mother. A chance of getting pregnant in case of diabetic women depends on the advancement of the disease. Persisting vascular and systemic disorders seen in diabetic mellitus are contraindications for pregnancy.
Subject(s)
Pregnancy in Diabetics/therapy , Prenatal Care , Female , Humans , Infant, Newborn , Pregnancy , Pregnancy Outcome , Pregnancy in Diabetics/complicationsABSTRACT
Health status of 53 babies delivered by diabetic mothers are discussed. Neonatal period was uncomplicated only in 12 cases. The remaining babies suffered from respiratory disorders, edema, neurological disturbances, prolonged jaundice, infections etc. Metabolic disorders in diabetic female are unfavourable for the development of pregnancy and neonate health. it may be improved by the proper diagnostico-therapeutical management prior to and during pregnancy and by intensive care of neonates after delivery. It requires, however, the establishment of health institution with highly qualified teams well equipped which will be able to carry out diagnosis and therapy of diabetes mellitus in females in the reproductive age, during pregnancy as well as proper care of the neonates.
