Leukocytes,human

Contamination of blood products with lymphocytes can lead to transfusion-induced reactions ranging from a mild fever to severe reactions such as alloimmunization and graft versus host disease (GvHD), in which the transfused lymphocytes (graft) survive the defensive immune reaction of the patient (host) and start a reaction which destroys the cells of the host. The patient also may develop an immune response to the human leukocyte antigen (HLA) type of the graft s cells and reject all platelet transfusions that do not match their own HLA system. The HLA system, found on blood platelets and lymphocytes, is more compHcated than, but similar to, the ABO blood group system of red cells. 

Transfusion-induced autoimmune disease has been a significant complication in the treatment of patients who require multiple platelet transfusions. Platelets and lymphocytes carry their own blood group system, ie, the human leukocyte antigen (HLA) system, and it can be difficult to find an HLA matched donor. A mismatched platelet transfusion does not induce immediate adverse reactions, but may cause the patient to become refractory to the HLA type of the transfused platelets. The next time platelets with an HLA type similar to that of the transfused platelets are transfused, they are rejected by the patient and thus have no clinical efficacy. Exposure to platelets originating from different donors is minimized by the use of apheresis platelets. One transfusable dose (unit) of apheresis platelets contains 3-5 x 10 platelets. An equal dose of platelets from whole blood donation requires platelets from six to eight units of whole blood. Furthermore, platelets can be donated every 10 days, versus 10 weeks for whole blood donations. 

Figure 15.6 Chromatogram of a plasma standard of human leukocyte elastase inhibitors obtained by using LC-LC. Adapted from Journal of Liquid Chromatography and Related Technologies, 19, R. A. Earley and L. R Tini, Versatile multidimensional chromatographic system for di ug discovery as exemplified by the analysis of a non-peptidic inhibitor of human leukocyte elastase , pp. 2527-2540, 1996, by courtesy of Marcel DekkeiTnc.

Park BH, Lee TP. 1978. Effects of pesticides on human leukocyte function. In Asher IM, ed., Proc 4th FDA Science Symposium, Annapolis, MD 273-274. 

Nagata S, Taira H, Hall A, Johnsrud L, Streuli M, Ecsodi J, Boll W, CanteU K, Weissmann C (1980) Synthesis in E. coli of a polypeptide with human leukocyte interferon activity. Nature 284 316-320... 

All the jellyfish venoms are toxic but also stimulate the cell mediated and humoral immunological systems of man. After injection of large doses of jellyfish venom into human skin, a perivascular mononuclear cell infiltration appears within the dermis. This infiltration is composed predominantly of helper inducer cells which produce suppressor activity. It appears that the NK enhancement of human leukocytes in patients envenomated by Chrysaora quinquecirrha is depressed when the clinical lesion is inflammatory (10). Recovery from this suppression follows the amelioration of the acute cutaneous reaction. In other instances, envenomated patients have abnormal macrophage migration tests (11). 

Goeddel D.V., Yelverton E., Ullrich A, Heyneker H.L., Miozzari G., Holmes W., Seeburg P.J., Dull T., May L, Stebbing N., Crea R., Maeda S., McCandliss R, Sloma A, Tabor J.M., Gross M., Eamilletti P.C. Pestka S. (1980) Human leukocyte interferon produced by E. coli is biologically active. Nature, 287,411-416. 

Birnboim, H.C. (1988). A superoxide anion induced DNA strand-break metabolic pathway in human leukocytes effect of vanadium. Biochem. Cell. Biol. 66, 374-381. 

Irreversible inhibition is probably due to the alkylation of a histidine residue.43 Chymotrypsin is selectively inactivated with no or poor inhibition of human leukocyte elastase (HLE) with a major difference the inactivation of HLE is transient.42,43 The calculated intrinsic reactivity of the coumarin derivatives, using a model of a nucleophilic reaction between the ligand and the methanol-water pair, indicates that the inhibitor potency cannot be explained solely by differences in the reactivity of the lactonic carbonyl group toward the nucleophilic attack 43 Studies on pyridyl esters of 6-(chloromethyl)-2-oxo-2//-1 -benzopyran-3-carboxylic acid (5 and 6, Fig. 11.5) and related structures having various substituents at the 6-position (7, Fig. 11.5) revealed that compounds 5 and 6 are powerful inhibitors of human leukocyte elastase and a-chymotrypsin thrombin is inhibited in some cases whereas trypsin is not inhibited.21... 

Finally, coumarin derivatives may act as general inhibitors of serine proteases or as specific inhibitors of human leukocyte elastase, depending on the nature of the substituents, through two distinct mechanisms, suicide substrates (a-chymotrypsin)... 

TABLE 11.1 Inhibition of a-Chymotrypsin and Human Leukocyte Elastase by Phenolic Esters of 6-(Chloromethyl)-2-oxo-2H-l-Benzopyran-3-Carboxylic Acid42... 

TABLE 11.2 Inhibition of Human Leukocyte Elastase, a-Chymotrypsin and Thrombin by 5 -Chloropyrid-3 -yl Derivatives at pH 8.0 and 25°C21... 

The acyl-enzyme can eliminate the 4-chlorine atom to generate this reactive intermediate that can then react with a nearby nucleophile such as His57 to give an alkylated acyl-enzyme derivative in which the inhibitor moiety is bound to the enzyme by two covalent bonds (Scheme 11.5). Inhibition is irreversible.59 The mechanism has been confirmed by X-ray structural analysis of protease-isocoumarin complexes. There is a cross-link between the inhibitor and the Serl95 and His57 residues of PPE.60 Human leukocyte elastase is also very efficiently inactivated.61... 

Human leukocyte elastase is a protease that degrades elastin and other connective tissue components. It is implicated in the pathogenesis of pulmonary emphysema and other inflammatory diseases such as rheumatoid arthritis and cystic fibrosis. Porcine pancreatic elastase has often been used as a model for HLE. Both enzymes have a small primary binding site Si. 

Doucet, C. Pochet, L. Thierry, N. Pirotte, B. Delarge, J. Reboud-Ravaux, M. 6-Substituted 2-OXO-2H-1 -benzopyran-3-carboxyI ic acid as a core structure for specific inhibitors of human leukocyte elastase. J. Med. Chem. 1999, 42, 4161—4171. 

Pochet, L. Doucet, C. Dive, G. Wooters,J. Masereel, B. Reboud-Ravaux,M. Pirotte, B. Coumarinic derivatives as mechanism-based inhibitors of a-chymotrypsin and human leukocyte elastase. Bioorg. Med. Chem. 2000, 8, 1489-1501. 

Vergely, I. Laugaa, P. Reboud-Ravaux, M. Interaction of human leukocyte elastase with a /V-aryl azetidinone suicide substrate conformational analyses based on the mechanism of action of serine proteinases. j. Mol. Graphics 1996, 14, 158-167. 

The inflammatory response in UC is propagated by atypical type 2 helper T cells that produce proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF).7 As discussed previously, a genetic predisposition to UC may partially explain the development of excessive colonic and rectal inflammation. The finding of positive perinuclear antineutrophil cytoplasmic antibodies (pANCA) in association with the human leukocyte antigen (HLA)-DR2 allele in a large percentage of patients with UC supports this theory.4,12... 

Family history of RA. Genetic studies demonstrate a strong correlation between RA and the presence of major histocompatibility complex class II human leukocyte antigens (HLA), specifically HLA-DR1 and HLA-DR4.4,5 HLA is a molecule associated with the presentation of antigens to T lymphocytes. 

Fi02 Fraction of inspired oxygen HLA Human leukocyte antigen human lymphocyte antigen... 

Human leukocyte antigens (HLA) Groups of genes found on the major histocompatibility complex, which contain cell-surface antigen-presenting proteins. The body uses HLA to distinguish between self-cells and non-self-cells. 

B53. Burger, A. G., Engler, D., Buergi, U Weissel, M., and Steiger, G Ether link cleavage is the major pathway of iodothyronine metabolism in the phagocytosing human leukocyte and also occurs in vivo in the rat. J. Clin. Invest. 71,935-949 (1983). 

The CB2 receptor has a more limited distribution, being localized predominantly in the immune system. Among the human leukocytes, B lymphocytes express the highest levels of CB2, followed respectively by natural killer cells, monocytes, polymorphonuclear neutrophils, T8 lymphocytes, and T4 lymphocytes. It is also found in the lymph nodes, spleen, tonsils, and thymus (Cabral, 1999). 

This approach has been mainly applied to peptide-based inhibitors of proteases, where the inhibitory molecule is a peptide with a transition state isostere appended to it, and the cognate substrate is simply a peptide of the same amino acid sequence, but lacking the isostere functionality. Examples where good correlations between the free energy of inhibitor binding and the free energy of kcJKM have been found, include peptide-trifluoromethyl ketone inhibitors of human leukocyte elastase (Stein et al., 1987) and peptide-phosphonamidate inhibitors of the metalloprotease ther-molysin (Bartlett and Marlowe, 1983). 

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