Effect of liver transplantation on tuftsin activity and phagocytic activity of neutrophil granulocytes in patients with liver cirrhosis.

BACKGROUND: Tuftsin activity (TA) is reduced in cirrhosis. This contributes to the defective phagocytic activity (PA) of neutrophil granulocytes and is related to the impairment of splenic function. Orthotopic liver transplantation (OLT) cures cirrhosis and might restore TA. This study was aimed at determining if OLT restores TA and PA. METHODS: We measured in 9 cirrhotic patients, before and after successful OLT, TA by a bioassay and PA by chemiluminescence in which neutrophils of the patient were tested with both autologous (PA1) and pooled sera from healthy subjects (PA2). Splenic function was assayed by the pitted red cell count. RESULTS: Before OLT, TA was reduced in 7 patients, and PA1 in all the patients. Pitted cell count was elevated in all the patients. After OLT (median 39 months; range 21-49), TA improved in all cases [median: from 8% (5-16%) to 20% (9-22%), p < 0.008], normalizing in 5 out of the 7 patients with low values. PA1 improved in all the patients [from 102 cpm (65-128 cpm) to 235 cpm (78-280 cpm), p < 0.008], normalizing in 5. Pitted red count decreased in 7 patients and normalized in 3 [from 3.3% (2.1-6.0%) to 2.4% (1.4-2.8%), p < 0.021]. Platelet count [from 55 x 10(3) (30-100) to 185 x 10(3) (93-286), p < 0.008] and leucocyte count [from 3.60 x 10(3) (1.81-5.23) to 5.53 x 10(3) (3.31-6.71), p < 0.008] also improved. CONCLUSIONS: OLT improves TA and PA of cirrhotic patients. This effect is associated with an improvement of both functional hyposplenism and haematological hypersplenism. The restoration of natural defences against infections may mitigate the adverse effect of immunosuppressive treatment.

Impaired tuftsin activity in cirrhosis: relationship with splenic function and clinical outcome.

BACKGROUND: Cirrhotic patients show increased susceptibility to bacterial infections. It is not known whether tuftsin deficiency, which is associated with an increased incidence of infections in many disease states, is present in cirrhosis. Our aims were to determine whether tuftsin activity is deficient in cirrhosis and if so, whether this deficiency is related to splenic function, contributes to altered neutrophil granulocyte function, or influences the occurrence of bacterial infections and patient survival. METHODS: Tuftsin activity and splenic function were assessed in 31 patients with liver cirrhosis and 31 healthy subjects. The phagocytic activity of neutrophil granulocytes from 23 patients was tested in vitro with addition of both autologous and pooled sera from healthy subjects. In 10 patients and eight controls it was also tested with addition of synthetic tuftsin. Patients were followed up until death or liver transplantation. RESULTS: Patients had reduced tuftsin activity (median 8% (range 3-24.5)) compared with controls (17% (11.5-37)) (p<0.001) and a higher pitted red cell count (p<0.001). Tuftsin activity was correlated with pitted cell count (p=0.02) and the Child-Pugh score (p=0.002). Nineteen of 23 patients showed deficient phagocytic activity of neutrophil granulocytes, which was correlated with tuftsin activity (p<0.001), improved in all cases but one with addition of serum from healthy subjects, and normalised with addition of synthetic tuftsin. Reduced tuftsin activity did not influence patient survival but was associated with a higher incidence of bacterial infections (p=0.029). COMMENT: Tuftsin activity was reduced in cirrhosis, and contributed to impaired phagocytic activity of neutrophil granulocytes. Such an abnormality appears to be related to impaired splenic function and severity of cirrhosis, and probably favours the occurrence of bacterial infections.

Impaired splenic function and tuftsin deficiency in patients with intestinal failure on long term intravenous nutrition.

BACKGROUND: Reticuloendothelial system function is impaired in humans receiving lipid regimens. AIMS: To evaluate the effects of long term administration of long chain triglyceride emulsions on reticuloendothelial system function. METHODS: Splenic function and tuftsin activity were measured in 20 patients on intravenous nutrition for intestinal failure, 20 patients with Crohn's disease who were not receiving intravenous nutrition, and 50 healthy controls. RESULTS: Pitted red cells counts in patients on intravenous nutrition (8.0%) were significantly higher (p<0.001) than in healthy controls (0.6%) and in patients with Crohn's disease (0.9%). No difference was found between healthy controls and patients with Crohn's disease. There was a correlation (r=0.50; p<0.03) between percentage of pitted red cells and duration of intravenous nutrition. Tuftsin activity was significantly reduced in the intravenous nutrition patient group (6%) compared with both disease controls (16.5%, p<0.01) and healthy volunteers (17.8%, p<0.001). An inverse correlation between tuftsin activity and pitted red cell percentage was found in the patients on intravenous nutrition (r(s) =-0.44, p<0.05). No relation was found in the patients on intravenous nutrition between pitted red cell percentage or tuftsin activity and type of disease, percentage of ideal body weight, residual length of small intestine, or administration (quantity and frequency) of lipid emulsion. Eight patients on intravenous nutrition had serious infections within the previous 12 months. CONCLUSIONS: Patients with a short bowel treated with long term intravenous nutrition have impaired splenic function, reduced tuftsin activity, and an increased risk of infection.

Splenic autotransplantation after abdominal trauma in childhood. Clinical and experimental data.

Splenectomy is known to increase the risk of overwhelming bacterial infection. There is a decrease in immunoglobulin IgM and T-lymphocytes, primary antibody response to antigen challenge is impaired, altered opsonic function an Tuftsin deficiency are noted. Splenic autotransplantation has been suggested as a method of preserving function and this concept is supported by experiments in animals. Prior to operation on humans the technique was thoroughly elaborated and practised in animal experiments (dogs). After splenectomy, 6-8 thin segments (Furka's "spleen chip") are placed in between the plates of the major omentum. Within the period of ten years out of 52 patients 11 children (4 girls, 7 boys) suffered from abdominal trauma underwent total splenectomy, and than autotransplantation in the Kenézy Hospital in Debrecen, Hungary. In several patients the postoperative follow-up radionuclide imaging, IgM, and Tuftsin levels, and the haematological changes (leukocytes, differential blood count, platelet count, iron level in serum) unambiguously confirmed the function of the splenic tissue.

Tuftsin deficiency in AIDS.

Tuftsin is an endogenous tetrapeptide that stimulates phagocytosis and is released from the Fc fragment of IgG by a splenic endocarboxypeptidase. Tuftsin activity and splenic function were measured in 21 patients with AIDS, 7 patients with AIDS-related complex (ARC), 22 patients who had undergone splenectomy, and 37 healthy volunteers. There was a significant inverse correlation between tuftsin activity and splenic function in all subjects. Tuftsin activity was significantly lower in patients with AIDS, ARC, and in those who had undergone splenectomy compared with healthy volunteers. Tuftsin deficiency may contribute to the risk of bacterial infection in symptomatic HIV-positive individuals.

[Tuftsin]. / Tuftsin.

Literature review. The tetrapeptide tuftsin (Thr-Lys-Pro-Arg) is cleaved off the carrier IgG molecule enzymatically and stimulates the phagocytic and bactericidal activity of polymorphonuclear leucocytes and macrophages. The action of tuftsin is mediated by specific receptor sites on the surface of these cells. Its antitumor activity has been shown in vitro as well as in vivo. The influence of tuftsin on the major metabolic processes of the cell (hexosemonophosphate shunt; cAMP/cGMP; Ca++-distribution; redox reactions) is the basis of its mode of action.--The feature of tuftsin and its low toxicity make it a useful agent for immunotherapy.

Tuftsin, a natural activator of phagocyte cells: an overview.

The recognition that a small oligopeptide was responsible for the full stimulation effect of specific cytophilic gamma-globulin on blood neutrophils arose from a study of the kinetics of phagocytosis. These were unusual in that the stimulation was short lived and that preincubation of the phagocyte with the gamma-globulin rendered the latter inactive. The oligopeptide was isolated, its structure determined (Thr-Lys-Pro-Arg) and synthesized. The discovery of human mutants with tuftsin deficiency exhibiting signs and symptoms of frequent severe infection further emphasized the specific biological function of the tetrapeptide. The mutant peptide was isolated, sequenced (Thr-Glu-Pro-Arg), and synthesized. Further studies showed that tuftsin requires two enzymes for its liberation from the parent carrier gamma-globulin. One enzyme is in the spleen that cleaves distal to the arginine end, and the other, on the outer side of the plasma membrane, cleaves proximal to the threonine residue. The tetrapeptide tuftsin stimulates all functions of phagocytic cells: phagocytosis, pinocytosis, motility, immunogenic activity including processing of the antigen and augmentation of the number of antibody-forming cells, bactericidal activity, and, above all, tumoricidal activity. The latter has been shown by several laboratories.

Congenital tuftsin deficiency.

The serum tuftsin activity in four different pediatric groups has been studied: (a) 20 premature infants, (b) 20 full-term infants, (c) 20 normal children (controls), and (d) 5 patients with recurrent and severe infections of the respiratory system, skin, and lymph nodes. The normal children as well as the premature and full-term infants had normal tuftsin activity. Tuftsin activity in the serum of the 5 patients in group (d) was absent. Cellular and humoral immunity in these patients was normal. All patients have been shown to have a mutant peptide that is strongly inhibitory to the normal tetrapeptide tuftsin. The clinical response of these patients to gamma-globulin was excellent.

Molecular basis of familial and acquired phagocytosis deficiency involving the tetrapeptide, thr-lys-pro-arg, tuftsin.

The biological activity and metabolism of the phagocytosis stimulating tetrapeptide (Thr-Lys-Pro-Arg) tuftsin, are discussed. Its effect is shown to be highly specific. It stimulates the phagocytic activity of the blood polymorphonuclear leukocyte. A unique familial deficiency of the tetrapeptide is described. In such patients, moderate to severe infections occur at high frequency. These are most pronounced in children. Biochemical and symptomatic evidence can readily be obtained in one or more children. At least one parent of either sex shows clinical signs or laboratory evidence of defective phagocytosis. Another type of deficiency results from removal of the spleen or from loss of specific function due to leukemic infiltration or embolism.

Defective phagocytosis due to deficiencies involving the tetrapeptide tuftsin.

A description of the symptoms and causes of tuftsin deficiency is presented. Two major causes which give rise to a deficiency of the tetrapeptide (thr-lys-pro-arg) are discussed. One is familial tuftsin deficiency syndrome that results from an inherited mutation involving the tetrapeptide. All patients give a history of repeated infection with variable severity. One parent, father or mother, is deficient and occasionally other siblings may have the disease. The other type of deficiency is the result of loss of splenic function whether it is due to surgical removal of the spleen and to infarction or infiltration of the organ. A method for the assay of tuftsin activity is described.

[Granulocyte dysfunction. I. Inborn defects (author's transl)]. / Granulocytendyfunktion. I. Angeborene Störungen

The insight in the function and dysfunction of granulocytes lately arouses more and more interest. This report summarises our present knowledge. In the first of two chapters the authors review the molecular basis of granulocyte function and the inborn defects of chemotaxis, opsonisation, phagocytosis and intracellular killing of bacteria and fungi.