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PubMed1982

Tuftsin analogs for probing its specific receptor site on phagocytic cells.

Six new analogs of the phagocytosis-stimulating peptide tuftsin were synthesized with the eventual aim of characterizing and isolating the tuftsin receptor. These analogs can be classified as follows: (a) photoaffinity labelling analogs for the specific covalent attachment to the tuftsin receptor: (b) fluorescent analogs containing either rhodamine or dansyl fluorescent probes for microscopic visualization of the tuftsin receptor; (c) biotin analog for separation and purification of the receptor by affinity methods. In this paper we describe the various synthetic pathways employed to introduce sensitive prosthetic groups into the tuftsin molecule while preserving its biological activity. Activities of the various analogs synthesized as compared to tuftsin in biological and receptor-binding assays are described. All analogs are able to stimulate phagocytosis of the macrophage cell as well as complete specifically for tuftsin binding sites on these cells.

Affinity Labels↗
PubMed1983

A biochemical study of the phagocytic activities of tuftsin and its analogues.

The effects of tuftsin and one of its analogues (4 [lys]-tuftsin) on phagocytosis of Staphylococcus aureus and Candida albicans were investigated in mice and rabbits. Mice were intravenously or orally administered 1-25 mg of 4 [lys]-tuftsin per kg daily for 4 to 7 days. After the mice were further treated with cyclophosphamide, they were intravenously challenged with C. albicans. More than 50% of the mice infected with C. albicans were killed within 7 days, although only 20% to 40% of those infected with the same microbes after 4 [lys]-tuftsin treatment died. A combination of 4 [lys]-tuftsin and an antibiotic was found to be somewhat more effective than either one alone. Further, pretreatment with 4 [lys]-tuftsin depressed microbial growth in the kidneys of mice bearing S-180 tumors. Rabbit peritoneal macrophages and polymorphonuclear leukocytes were harvested by intraperitoneal injection of liquid paraffin and of glycogen solution, respectively. For in vitro study of phagocytosis, rabbit macrophages of polymorphonuclear leukocytes were incubated in Hanks solution together with S. aureus and the number of survivors was determined. Enhanced engulfing activity of macrophages and increased bactericidal activity of polymorphonuclear leukocytes were shown by the in vitro phagocytosis experiments. It is expected that 4 [lys]-tuftsin will be effective against infectious disease, especially in immunocompromised hosts such as patients with malignant tumors.

Animals↗
PubMedDate not supplied

Stability of sterile saline solutions of synthetic tuftsin, a naturally occurring immunomodulating peptide.

Tuftsin, Thr-Lys-Pro-Arg, is a natural immunomodulating peptide originally found as a phagocytosis-stimulating factor for polymorphonuclear leukocytes. The peptide is now known to elicit various other activities including antimicrobial, antiviral and antitumor effects in vivo. Preliminary human studies revealed antitumor and anti-AIDS activities. In view of this clinical potential, we performed studies on the stability of sterile saline solutions of tuftsin stored at 25 degrees C, 5 degrees C, -20 degrees C or -70 degrees C utilizing a phagocytosis assay and analytical HPLC. Tuftsin stored at -20 degrees C or -70 degrees C gradually lost its phagocytosis-stimulating activity; tuftsin stored at 25 degrees C or 5 degrees C lost its phagocytosis activity rather rapidly. By 6 months, tuftsin stored at 25 degrees C lost all activity, and by 12 months, it significantly inhibited phagocytosis. In contrast, HPLC analysis indicated very minor changes. While tuftsin stored at 25 degrees C lost almost all activity by 6 months, we detected appearance of only 1% impurities by HPLC. This study indicates that if its activity is to be preserved, solutions of tuftsin must be frozen for storage.

Adjuvants, Immunologic↗
PubMed1988

Substance P augmentation of CSF-1-stimulated in vitro myelopoiesis. A two-signal progenitor restricted, tuftsin-like effect.

The inflammatory neuropeptide substance P acted as a costimulant for macrophage CSF-1-induced clonal proliferation of murine marrow-derived two signal-dependent mononuclear phagocyte progenitors. Substance P had no effect on clonal proliferation by progenitors responding solely to CSF-1. Substance P fragment 2-11 had no costimulatory activity; however, SP fragment 1-4 retained the full activity of the parent undecapeptide. Fragment 1-4 (ARG-PRO-LYS-PRO), a peptide containing a PRO residue between two positive charges, is a tuftsin-like (THR-LYS-PRO-ARG) tetrapeptide, and tuftsin exerted an identical costimulatory effect. Substance P, SP:1-4, and tuftsin were optimally effective as costimulants at 10(-7) to 10(-6) M. (ALA1)-tuftsin, an inhibitory analog of tuftsin, was a potent negative regulator of two signal-dependent colony formation. (ALA1)-tuftsin at concentrations less than or equal to 10(-9) M exerted dose-dependent inhibition of the positive effects of optimal concentrations of all of the co-stimulants tested, including bacterial LPS. The inhibitory tetrapeptide was equivalent in activity to ferritin, an established inhibitor of two signal-dependent colony formation. The results indicated that SP may influence myelopoiesis in addition to its other inflammatory and immunopotentiating properties. In addition, a potentially valuable modulator of SP and LPS responses in this system, (ALA1)-tuftsin, was identified.

Amino Acid Sequence↗
PubMed1981

Tuftsin, a natural activator of phagocytic functions including tumoricidal activity.

Some of the properties of the tetrapeptide tuftsin, Thr-Lys-Pro-Arg, are discussed. We describe three phases of tuftsin activation of the macrophage. Tuftsinyltuftsin, the octapeptide Thr-Lys-Pro-Arg-Thr-Lys-Pro-Arg, was synthesized with a view of minimizing the formation of Lys-Pro-Arg, from tuftsin by tissue aminopeptidases. The tripeptide is a tuftsin inhibitor. The octapeptide proved to be quite effective in prolonging the life of syngeneic mice injected with L1210 leukemia cells. Its effect in our laboratory, was considerably better than we could obtain with tuftsin. A simple method for purifying tuftsin by high performance liquid chromatography is described using 0.75% trifluoroacetic acid in water. The tuftsin sequence Thr-Lys-Pro-Arg is present in P12 protein of Rausher murine leukemia virus. A close analog Thr-Arg-Pro-Lys appears in yet another virus protein the haemagglutinin of influenza virus. A second close analog Thr-Arg-Pro-Arg forms the penultimate carboxyterminal of a pancreatic polypeptide found in human and several animals.

Animals↗
PubMed1975

The effect of Tuftsin on the nitrous blue tetrazolium reduction of normal human polymorphonuclear leukocytes.

The influence of Tuftsin, the synthetic phagocytosis-stimulating tetrapeptide (L-threonyl-L-lysyl-L-prolyl-L-arginine), on the nitrous blue tetrazolium (NBT) reduction by human polymorphonuclear leukocytes was investigated. It was found that this substance increases the NBT reduction by approximately as much as endotoxin. Other tetrapeptides do not share this property. When Tuftsin analogs are added to the cell suspension and incubated, they prevent the action of both Tuftsin and endotoxin but not of methylene blue. When washed of the analogs, the cells regain the property to be activated by both Tuftsin and endotoxin. It appears that methylene blue on one hand and Tuftsin and endotoxin on the other hand have different sites for their actions. We suggest that whereas methylene blue diffuses into the cell and acts directly upon the hexosemonophosphate shunt activation, Tuftsin and endotoxin appear to act on the cell membrane binding to specific receptors. By treating the cells with Tuftsin analogs, we probably block these receptors.

Arginine↗
PubMed1994

Splenic autotransplantation after splenectomy: tuftsin activity correlates with residual splenic function.

This study set out to determine the relationship between splenic function (as assessed by the percentage of pitted red cells) and tuftsin activity, and to confirm the return of effective splenic function after splenectomy for trauma. Twenty-three patients (13 men) took part. Ten of mean age 48.5 (range 30-74) years had had the spleen removed for traumatic rupture and 13 of mean age 49.7 (range 23-66) years had undergone elective splenectomy. At the time of the study all patients had had the spleen removed a minimum of 1 year previously (mean 6.1 (range 1-15) years). Fifty healthy volunteers matched for sex and age were also studied. In each subject, residual splenic function was evaluated by counting the percentage of pitted red cells. Tuftsin activity was also determined. A highly significant negative correlation was found between pitted red cell percentage and tuftsin activity (rs = -0.80, P < 0.001). Compared with healthy controls (mean 21.6 (range 13-37) per cent), tuftsin activity was significantly reduced both in patients who had undergone splenectomy for trauma (mean 4.4 (range 0-9) per cent; P < 0.0001) and in those who had had elective splenectomy (mean 0; P < 0.0001). Tuftsin activity was significantly (P < 0.001) more depressed after elective than traumatic splenectomy. These data confirm a decrease in tuftsin activity following splenectomy and show that this deficit is significantly greater after elective than emergency removal. These observations confirm that residual splenic function is often present after traumatic splenectomy.

Adult↗
PubMed1984

Tuftsin (Thr-Lys-Pro-Arg), a natural modulator of macrophage activity: further studies.

Tuftsin, Thr-Lys-Pro-Arg, that activates macrophage functions, binds to specific receptors on these cells. The receptor capacity to bind tuftsin is diminished by prior treatment of the cells with dithiothreitol. Adherent mouse peritoneal macrophages bind tuftsin to a far less extent than non-adherent macrophages. Michaelis constant (Km) of tuftsin for phagocytic stimulation of macrophages is 111 eta M. The half maximal binding concentration of tuftsin by these cells is 117 eta M. These are similar values and indicate that full occupancy of the receptors by tuftsin is a necessary prerequisite for maximal phagocytosis.

Animals↗
PubMed1989

Specific translocation of tuftsin (Thr-Lys-Pro-Arg), a natural immunomodulating peptide, into the nuclei of human monocytes.

To delineate the mechanism of growth and differentiation activities of tuftsin (Thr-Lys-Pro-Arg), we examined the translocation of tuftsin after internalization by the target cells. We found using two independent techniques, fluorescence microscopy and autoradiography, that while in human polymorphonuclear leukocytes (terminally differentiated cells) the peptide remains in the cytoplasmic compartment, in monocytes it translocates to the nucleus. The ability of tuftsin to directly interact with DNA was documented by a large increase in the melting point of bovine DNA in the presence of tuftsin. It is suggested that the translocation, processing and action of tuftsin may depend on the differentiation state and/or on the type of effector cells. Also, tuftsin has the capacity to interact directly with DNA and, therefore, may have a potential for affecting gene activity.

Autoradiography↗
PubMed1984

The effect of tuftsin and splenectomy on mortality after intraabdominal sepsis.

A murine model of cecal ligation and puncture (CLP) was used to test the effect of tuftsin, with or without splenectomy, on mortality following intraabdominal sepsis. There were no deaths among shamoperated control mice after ether anesthesia, whereas CLP produced an 100% mortality by 24 hr. When CLP was followed at 16 hr by excision of the cecum and saline peritoneal lavage, the mortality rate was 20% at 24 hr and 60% at 72 hr. When tuftsin (1 mg/kg) was given only at 0, 12, and 24 hr in the CLPE model, the mortality rates were not significantly lower than CLPE alone (10% at 24 hr, 40% at 72 hr). When the tuftsin dose was increased to every 12 hr for 3 days, the mortality fell significantly to 0 and 13.5% at 24 and 72 hr (P less than 0.05 chi 2 vs CLPE ). Splenectomy 2 weeks prior to CLPE did not alter mortality (11% at 24 hr, 53% at 72 hr). When tuftsin was administered to the splenectomized animals undergoing CLPE , mortality did not change significantly (13.5% at 24 hr, 38% at 72 hr). These data suggest that tuftsin can confer protection from sepsis in animals with normal spleens, but it must be given longitudinally to be effective optimally. Splenectomy followed 2 weeks later by CLPE did not lead to increased mortality, and tuftsin did not reduce mortality in the asplenic animal.

Abdomen↗
PubMed1993

Modulation of the intracellular survival of Brucella abortus by tuftsin and muramyl dipeptide.

Tuftsin, a physiologic bioactive peptide of animal origin, and muramyl dipeptide, a synthetic bioactive glycopeptide of microbial origin, are known to enhance several recognized macrophage functions and increase non-specific resistance of the host against a number of pathogens. The influence of these two bioactive peptides was studied in permissive bovine mammary macrophages that were unable to control the intracellular replication of Brucella abortus and restrictive bovine mammary macrophages that were able to effectively reduce the intracellular survival of B. abortus. Addition of tuftsin (Thr-Lys-Pro-Arg) or muramyl dipeptide significantly (P < 0.03) enhanced the ability of the permissive macrophages to control the intracellular replication of B. abortus strain 2308 and resulted in the functional conversion of the permissive macrophages into restrictive macrophages. Addition of tripeptide tuftsin fragment (Lys-Pro-Arg), a natural inhibitor of tuftsin, to the medium completely abrogated the effect of tuftsin (P < 0.03). No additive effect on the ability of the macrophages to control the survival of B. abortus resulted from the combination of tuftsin and muramyl dipeptide.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1992

Effect of tuftsin and its retro-inverso analogue on the release of interferon (IFN-gamma) and tumor necrosis factor (TNF-alpha) by human leucocytes.

The aim of this work was to demonstrate whether natural tuftsin or a retro-inverso (r.i.) analogue may induce interferon (IFN) and tumor necrosis factor (TNF) in peripheral-blood-mononuclear-cells (PBMC). For this purpose tuftsin or its analogue were added at different molar concentrations to PBMC and the supernatants were tested for IFN and TNF activity. Both cytokines were released after 12 hours incubation with r.i. tuftsin at an optimum concentration of 10(-10) M. Under the same conditions no activity was observed in the presence of natural tuftsin. In comparison to natural tuftsin the stimulatory activity of this tuftsin analogue is likely to be due to its high stability.

Adult↗
PubMed2005

Tuftsin-mediated immunoprophylaxis against an isolate of Aspergillus fumigatus shows less in vivo susceptibility to amphotericin B.

In the present study, we evaluated the immunopotentiating efficacy of tuftsin against experimental murine aspergillosis in both normal and immunodebilitant BALB/c mice. The animals were challenged with an isolate of Aspergillus fumigatus (1x10(8) cfu/mouse) that was showing less susceptibility to lower doses of amphotericin B in murine animal model. Co-administration of the immunomodulator tuftsin and liposomised-amphotericin B was found to be highly effective in the treatment of systemic infection of A. fumigatus in both immunocompetent and leukopenic mice. Moreover, pre-treatment of mice with liposomised-tuftsin prior to challenging them with A. fumigatus infection and subsequent treatment with tuftsin-bearing liposomised-amphotericin B was found to be extremely efficient in successful elimination of fungal pathogen. In another set of experiments, tuftsin-mediated antigen-specific memory antibody response was also assessed by immunizing the animals with A. fumigatus cytosolic antigen. The animals that received a booster 150 days after the first immunization with tuftsin-liposomes-antigen showed more resistance to A. fumigatus infection in comparison with the naïve animals.

Amphotericin B↗
PubMed2005

The immunomodulatory effects of tuftsin on the non-specific immune system of Indian Major carp, Labeo rohita.

The purpose of this study was to determine if injections of different dosages of tuftsin would enhance the immune response and disease resistance against the infections due to the opportunistic pathogens Aeromonas hydrophila and Edwardsiella tarda in Labeo rohita fingerlings. Hence, four different dosages of tuftsin in PBS suspension at the rate of 0, 5, 10, 15 mg kg(-1) body weight of fish were injected intraperitoneally to the fingerlings of L. rohita at 2-week intervals for four times. After every 2-week interval, different serum biochemical, haematological and immunological parameters of fish were evaluated. Biochemical and haematological parameters including serum total protein content, albumin content, globulin content, albulin:globulin ratio, glucose content, leucocyte counts etc.; cellular immune parameters including superoxide anion production, phagocytic activities, lymphokine production index etc.; humoral immune parameters including lysozyme activity, complement activity, serum bactericidal activity etc., in the fish were evaluated after every 2-week interval. After 56 days, fish were divided into two subgroups under each major treatment group for challenge with two pathogens A. hydrophila and E. tarda. The mortality (%) and agglutinating antibody titre was recorded on 28th day post challenge. Most of the immune parameters including leucocyte count, phagocytic ratio, phagocytic index, lysozyme activity, complement activity, and serum bactericidal activity were significantly (p<or=0.05) maximum on 42 days after three i.p. injections of 10 mg kg(-1) body weight of tuftsin. Challenge study indicated least mortality in the group of fish injected with 10 mg kg(-1) body weight of tuftsin for four times. Multiple injections of tuftsin might have maintained the activation of phagocytic cells for a long period, which in turn led to long-term protection in the fish. Thus, multiple injections of 10 mg kg(-1) body weight of tuftsin for three times can be advocated for enhancing the immune response of fish species under aquaculture.

Aeromonas hydrophila↗
PubMed1997

Tuftsin-THF-gamma 2 chimeric peptides: potential novel immunomodulators.

Synthesis of two chimeric peptides composed of tuftsin and thymic humoral factor-gamma 2 (THF-gamma 2) conjugates was accomplished. Our goal was the generation of novel immunomodulators. Initially, we demonstrate an IL-6 inducing activity of the phagocytic cells stimulant, tuftsin, on murine macrophages. This activity was documented only in the presence of antigen, either KLH or lysozyme. The augmentation was dose dependent, with optimal activity at a concentration of 200 and 20 nM, respectively. The chimeric peptides, either H2N-tuftsin-THF-gamma 2-OH or H2N-THF-gamma 2-tuftsin-OH, were also evaluated in the IL-6 system in the presence of the more potent antigen, KLH. The IL-6 inducing effect was maintained, although maximal activity appeared only at a concentration an order of magnitude greater than that of tuftsin. The chimeric peptides were further tested in an assay evaluating enhancement in murine bone marrow myeloid colony formation, a system in which THF-gamma 2, a T cell stimulant, has an established beneficial effect. The compounds were found to be inactive at the 25-200 ng/ml (14-112 nM) concentration range evaluated. Finally, the chimeric peptides were tested in a combined macrophages-T cells assay, i.e. antigen presentation, in which H2N-tuftsin-THF-gamma 2-OH was found to be more active than either parent peptide, thus representing a possible therapeutic agent.

Adjuvants, Immunologic↗
PubMed1986

Isolation and subunit composition of tuftsin receptor.

Tuftsin (Thr-Lys-Pro-Arg) receptor was purified to apparent homogeneity by affinity chromatography, using a pentapeptide analog (Thr-Lys-Pro-Pro-Arg) that binds the receptor more than 4 times as avidly as tuftsin. The analog was covalently linked to a solid support (Affi-Gel 10). Rabbit peritoneal granulocyte membrane solubilized with 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate was applied to the affinity column, the column was washed with 0.1 M ammonium carbonate (pH 7.9) and 0.1 M ammonium acetate (pH 5), and bound material was eluted with 20 nM tuftsin or pentapeptide. The eluate was concentrated and subjected to gel filtration; this yielded one major peak of [3H]tuftsin binding activity corresponding to approximately 500 kDa and a minor peak at approximately 250 kDa. Rechromatography of either peak resulted in the appearance of the same major and minor peaks. NaDodSO4/PAGE of the affinity-purified material under nonreducing conditions showed only two silver-staining bands. Electroblotting followed by [3H]tuftsin overlay and fluorography showed two adjacent radioactive bands corresponding in mobility to the silver-stained bands. Under reducing conditions, NaDodSO4/PAGE yielded molecular mass values 62 kDa and 52 kDa for the two tuftsin receptor subunits. Electron microscopy revealed a homogeneous population of spherical molecules with diameters of 104 A.

Animals↗
PubMed2002

Immunomodulator tuftsin augments anti-fungal activity of amphotericin B against experimental murine candidiasis.

In the present study, we report the potential of an immunomodulator tuftsin in increasing the efficacy of liposomised Amphotericin B (Amp B) against drug sensitive as well as drug resistant experimental murine candidiasis. The Amp B containing liposomes demonstrated strong potential of eliminating systemic candidiasis (70% survival) in animals infected with Amp B sensitive strain of Candida albicans (C. albicans). The same liposomal formulation was found to be ineffective in treatment of animals infected with drug resistant C. albicans. However, the co-administration of liposomal formulation of Amp B along with an immunomodulator tuftsin, was found to be competent enough in curing even the drug resistant candidiasis. In contrast, none of the animals survived in the control groups, which were treated with free or liposomised Amp B (without tuftsin). Further, the effect of liposomised tuftsin, on T-cell proliferation as well as antibody production reveals that tuftsin elicits strong immunopotentiating effects as well. The pretreatment with liposomised tuftsin prior to challenging the animals with drug resistant C. albicans infection has also been effective and shows an extra edge in prophylactic perspectives.

Adjuvants, Immunologic↗
PubMed1989

The lack of antigenicity of tuftsin: a naturally occurring phagocytosis stimulating tetrapeptide.

Tuftsin (Thr-Lys-Pro-Arg) is a naturally occurring tetrapeptide that stimulates all known functions of the polymorphonuclear leukocyte and macrophage cell lines. Tuftsin is located in the FC region of IgG between the 289 and 292 amino acid sequence of the CH2 domain. We describe unsuccessful attempts to generate antituftsin antibodies. In separate experiments tuftsin was chemically conjugated to methylated bovine serum albumin (CH3BSA), BSA, keyhole limpet hemocyanin (KLH) and purified protein derivative (PPD). Tuftsin was also polymerized with glutaraldehyde. Animals used for immunization were rabbits, roosters, and dogs. All experiments failed to produce antituftsin antibody. Probable reasons for the lack of antigenicity include: I) Lack of "foreignness" of tuftsin in mammal species. II) The small size of the tetrapeptide. III) Tuftsin may be exerting an adjuvant effect when coupled to foreign antigens and is therefore not recognized by the host immune system.

Animals↗