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PubMed1984

In vitro prostaglandin release from guinea pig parenchymal lung tissues is not stimulated by thymic peptides.

Prostaglandins (PGs) have been demonstrated to both enhance and inhibit immune responses. As several chemically distinct serum and thymic polypeptide preparations have been shown to stimulate immunologic reactivity in several cell populations, animal models, or clinical patient trials, we have investigated the capacity of these hormone-like products from the thymus and blood to modulate PGs generation/release in normal parenchymal lung tissues of the guinea pig. Several concentrations of thymosin fraction 5, serum thymic factor, tuftsin or thymopentin, as well as histamine or A23187 (as positive controls) were exogenously applied to parenchymal lung fragments in vitro, and supernatants analyzed for PG content by radioimmunoassay. No alteration in PG levels (enhancement or suppression) from basal (spontaneous) release was found. These findings suggest that during a 30-min incubation, all four polypeptide immunomodulators were ineffective in eliciting an immediate response in the arachidonic acid cascade via the cyclooxygenase pathway.

Animals↗
PubMed1986

Sensory neuropeptides (substance P) and 4-11 SP enhance human neutrophils chemiluminescence; the role of L-arginine.

Investigations on the effect of a naturally occurring neuropeptide, substance P (SP) and one of its synthetic analogues, 4-11 SP, on luminol-enhanced chemiluminescence (CL) of human polymorphonuclear leukocytes (PMN) are presented. Both peptides elicited a strong burst of CL with different time course and dose-response curves. SP- and tuftsin-induced CL were similar, both peptides sharing a Lys-Pro-Arg terminal; 4-11 SP, which lacks the terminal arginine, peaked earlier than the natural peptide. Surprisingly when PMN were pre-incubated with L-arginine (L-Arg) this enhancing effect was abolished or diminished. L-Arg and an L-Arg synthetic derivative (PCF-39) were also evaluated; PCF-39 strongly increased the PMN CL, while L-arginine showed a significant CL enhancement only in 43% of the donors tested. Peptide- and arginine-induced CL were Ca++/MG++ dependent.

Arginine↗
PubMed1991

Application of an anhydrotrypsin-immobilized precolumn for selective separation of peptides having arginine or lysine at their C-termini by column-switching high-performance liquid chromatography.

A column-switching high-performance liquid chromatographic (CS-HPLC) system which consisted of an anhydrotrypsin (AHT)-immobilized diol-silica precolumn and a reversed-phase analytical column was developed for the selective separation of peptides having Arg or Lys at their C-termini. Tuftsin (Thr-Lys-Pro-Arg) could be enriched almost quantitatively on the precolumn when loaded with water as a carrier solvent and the precolumn was washed with 10-30 mM acetate buffer (pH 5.0). An investigation of the affinity characteristics of 55 peptides to the AHT precolumn showed that among twelve peptides having Arg or ArgNH2 at their C-termini and more than four amino acid residues, ten were retained almost quantitatively on the precolumn, and eight out of nine peptides having Lys at their C-termini were less retained. The peptide having D-Arg at its C-termini was not retained. However, twelve out of thirty peptides having no Arg or Lys at their C-termini were also retained, but the retention was greatly decreased, in contrast to the Arg peptides, when the precolumn was washed with 20 mM calcium chloride solution. The results indicate that the CS-HPLC system equipped with an AHT precolumn offers new selectivity in the HPLC selectivity in the HPLC separation of peptides.

Amino Acid Sequence↗
PubMedDate not supplied

Studies of the influence of different cross-linking reagents on the immune response against a B-epitope.

We have previously shown that the carrier polytuftsin obtained by polycondensation of tuftsin, a naturally occurring macrophage activator, increases significantly the antibody response against a linked B-epitope. In the present work, we have studied the influence of different cross-linking reagents on the quality of the conjugation and on the immune response, at both B-cell and T-cell levels. We observed that the cross-linking method used for coupling the B-epitope to the carrier influences the immune response. A hypothesis is put forward to explain the differences observed.

Amino Acid Sequence↗
PubMedDate not supplied

"Meshed-Bag Gathered-Bunch" method for solid-phase synthesis of small molecular diverse compounds.

A new "Meshed-Bag Gathered-Bunch" technology for the solid-phase synthesis of chemical libraries was developed. Using such technology, we synthesized muramyl dipeptide mimetics including derivatives at the N- and C-terminus, cyclic muramyl dipeptide mimetics, muramyl dipeptide and Tuftsin's analogue conjugates. The advantages of such a method include ease of manufacture, low unit cost of production, the physical encoding method, and the compatibility with both parallel and "split-mix" approaches.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2004

Prophylactic role of immunomodulators in treatment of systemic candidiasis in leukopenic mice.

In the present study, we have evaluated prophylactic role of various immunomodulators viz. lipopolysachharide, protein A and tuftsin to impart protection against experimental candidiasis in leukopenic mice. Both free as well as liposomised form of nystatin was not effective enough in offering complete cure against less susceptible isolate of Candida albicans (JNMCR) infection in immunodebilitant mice. Interestingly, the pretreatment of leukopenic mice with immunomodulators before challenging them with C. albicans increased therapeutic efficacy of the nystatin against systemic candidiasis. Efficacy of the treatment was evaluated on the basis of survival of the animals as well as fungal load in systemic circulation and various organs viz. liver, kidney, spleen and lungs of the treated animals.

Amphotericin B↗
PubMed1999

Increase in the immunogenicity of HIV peptide antigens by chemical linkage to polytuftsin (TKPR40).

The use of synthetic peptide antigens in human prophylaxis still suffers from the very important problem of finding suitable carriers devoid of side effects. A desirable carrier for use in humans would be poorly immunogenic by itself, yet it would enhance the immune response to the peptide antigen. In the study reported herein, we examined the role of polytuftsin (TKPR40), a synthetic polymer of the natural immunomodulator tuftsin, as a carrier for synthetic peptides of HIV derived from the gp41 and gp120 proteins. Chimeric immunogens were constructed by chemical linkage between synthetic peptides of HIV and polytuftsin. These were employed for immunization of mice of different MHC haplotypes, and the humoral and cellular immune responses developed against the peptides were assessed by measuring total IgG, IgG, subclasses, T-cell proliferation, and in vitro cytokine release. A significantly stronger immune response was observed in mice immunized with the peptide-polytuftsin conjugates than in mice receiving the peptide dimers (peptide-peptide). Peptide-polytuftsin conjugates induced IgG2a and IgG2b isotype switching after both primary and secondary immunization. In addition, there was a positive correlation between the amounts of cytokines and the shift in the IgG isotypes. These data suggest that the use of polytuftsin as a carrier may increase the immune response against poorly immunogenic synthetic peptides.

AIDS Vaccines↗
PubMed1985

Serum factors for opsonisation of non-typable Haemophilus influenzae.

Neutrophil chemiluminescence was used to assess the opsonins required for phagocytosis of non-typable Haemophilus influenzae isolated from sputum samples of patients with hypogammaglobulinaemia. Immunoglobulin was the major opsonin, whereas complement was relatively unimportant. Evidence was found for a heat-labile opsonin other than complement that enhanced phagocytosis of these organisms. Tuftsin was shown to aid phagocytosis of H. influenzae without triggering chemiluminesence.

Agammaglobulinemia↗
PubMed1999

Potentiation of immune response against the RESA peptides of Plasmodium falciparum by incorporating a universal T-cell epitope (CS.T3) and an immunomodulator (polytuftsin), and delivery through liposomes.

Synthetic peptides representing repeat sequences of ring-infected erythrocyte surface antigen (RESA) of Plasmodium falciparum have shown poor immunogenicity and protection. In this study, the RESA peptides [(EENVEHDA)2 and (DDEHVEEPTVA)2] were chemically linked to a universal T-cell determinant, CS.T3, derived from the CS protein of P. falciparum. Polytuftsin (TKPR)40, a polymer of naturally occurring immunomodulator "tuftsin," was physically mixed with these conjugates. These preparations in alum and liposomes were immunized in four inbred strains of mice with different genetic backgrounds to study the humoral response. In the case of liposome-entrapped preparations, a 10 microg dose of antigen showed the optimum antibody response. Mice immunized with liposome containing RESA peptide(s)-CS.T3 conjugate along with polytuftsin showed the highest antibody levels in all the strains, whereas the RESA peptide(s) alone, adsorbed on alum or entrapped in liposomes, showed either poor or moderate antibody levels. The antibodies raised against liposome-entrapped preparations in both high-responder strain (SJL/J H-2s) and low-responder strain (FVB/J H-2q) showed 2 4-fold lower Kd values as compared to the alum adsorbed preparations, suggestive of high affinity antibodies. All the antigen preparations predominantly induced IgG2a and IgG2b isotype response, suggesting that the T-helper response involved is of the CD4 Thl type. The in vitro merozoite reinvasion inhibition assay showed 50-92% inhibition with sera raised against different antigen formulations. The highest percentage inhibition was observed with the RESA peptide-CS.T3 conjugate containing polytuftsin in liposomes. Thus, the incorporation of peptide antigens inside liposomes not only reduced the antigen dose by 5-fold but also elicited a high titre with high affinity antibodies and the inhibition of merozoites to RBC in vitro. Therefore, we conclude that the incorporation of these synthetic constructs in liposomes could be a useful strategy for the development of a subunit immunogen against malaria.

Adjuvants, Immunologic↗
PubMed1990

Interferon-gamma potentiates antibody affinity in mice with a genetically controlled defect in affinity maturation.

Interferon-gamma (IFN-gamma), the tetrapeptide tuftsin and the synthetic nonapeptide from interleukin-1 beta (IL-1 beta) (amino acids 163-171) have previously been shown to act on macrophages and/or T cells and to enhance antibody titres to T cell-dependent antigens. The ability of these immunomodulatory agents to potentiate antibody affinity in addition to antibody titre has been studied in a line of mice that fail to demonstrate normal maturation of antibody affinity (low N/M mice). The results presented here confirm that each of the agents potentiate antibody levels following simultaneous injection with a T cell-dependent antigen but demonstrate that only IFN-gamma is able to enhance antibody affinity in these mice. The observation that IFN-gamma can enhance both antibody affinity and antibody levels suggests that it could be an important adjuvant for vaccine use.

Adjuvants, Immunologic↗
PubMed1995

The immunomodulatory diversity of the proteins of the transforming growth factor beta (TGF beta) family.

The examination of immunomodulatory properties of oligopeptides derived from two exposed loops (containing thymopentin-like and tuftsin-like sequences, respectively) of the proteins belonging to TGF beta family suggests that the particular species of the TGF beta family should differ distinctly in their influence on the immune response. According to our results obtained from three TGF beta species of mammals, TGF beta 2 should be a strong immunosuppressor, whereas for TGF beta 3 the immunostimulative potency is more probable. TGF beta 1 species would possess both immunosuppressive and immunostimulative potency, residing in two different loops of the protein. The results obtained also suggest that chicken TGF beta 4 should be associated with immunostimulative effects and xenopus TGF beta 5 with immunosuppressive ones.

Adjuvants, Immunologic↗
PubMed1985

The effect of surgery on natural killer cell activity in head and neck cancer patients: in vitro reversal of a postoperatively suppressed immunosurveillance system.

Curative surgery diminished natural killer (NK) cell activity in 17 patients with previously untreated squamous cell carcinoma of the head and neck (37% +/- 17%, preoperatively vs. 21% +/- 11%, postoperatively; p less than 0.001). This operatively induced suppression was dependent on the presence of a nylon wool adherent cell population. With the removal of this surgically generated suppressor population from the in vitro assay, postoperative suppression of natural killer activity was significantly diminished (21% +/- 13%, vs. 30% +/- 23%, p less than 0.01). The capability of fully restoring postoperatively suppressed NK cell activity was subsequently demonstrated by the synergistic effect of removing a nylon wool adherent suppressor population and stimulating NK cells with a naturally occurring immunopotentiator, tuftsin (from 21% +/- 13% to 41% +/- 23%; p less than 0.0001). In utilizing biological response modifiers in the perioperative period in the cancer patient, the interaction of these agents and the surgically generated suppressor cell population needs to be considered.

Aged↗
PubMed2005

Synthesis of linear, branched, and cyclic peptide chimera.

Chimeric peptides are unnatural constructs consisting of bioactive compounds from at least two different peptide(s) and/or protein(s) or two sequences from different parts of the same protein. Such multifunctional peptide combinations are prepared to enhance the biological activity or selectivity of their components. New biological effects can also be achieved with the chimera. In this chapter the synthesis of three different types of chimeric peptides will be described. In a linear chimera, two peptide epitopes from different parts of glycoprotein D (gD) of herpes simplex virus (HSV) are combined. A branched chimera, built from linear peptides, consists of tuftsin oligomers with immunostimulatory activity and an epitope peptide of HSV gD. The third compound is a cyclic chimeric molecule, where alpha-conotoxin GI as a host peptide is modified by the incorporation of a core epitope from HSV gD as a guest sequence.

Amino Acid Sequence↗
PubMed2005

[Evaluation of the effect of splenectomy with autologous spleen tissue implantation in some monocyte functions in children with hepatosplenic schistosomiasis mansoni].

Adherence index, superoxide and TNF-alpha production in monocytes, with or without tuftsin treatment, were investigated in hepatosplenic schistosomiasis mansoni bearers with splenectomy with or without autologous implantation of spleen tissue. Three groups were evaluated: Healthy volunteers control group (CG) (n=12); Splenectomy with seft auto-transplant AG (n=18) and Splenectomy without auto-transplant WAG (n=9). Adherence index and TNF-alpha did not differ among the groups. Superoxide production was similar in CG and AG, in the 1st hour after cell stimulation. SP was larger in each hour time in CG and AG groups as compared WAS group. TT recovered normal pattern of SP in AG comparable with levels found in CG, with increase from the 1st to 2nd hour. However, TT did not alter SP in WAG, which remained reduced in all time points. Autologous implantation of spleen tissue seems to contribute for recovery and maintenance of the evaluated immunological reactions, which might be important in response to infections.

Adolescent↗
PubMed1994

Dituftsin and polytuftsin induce an anti-peptide IgG response to non-immunogenic peptides in mice.

The effect of covalently attaching multiple forms of the immunomodulating tetrapeptide tuftsin to normally non-immunogenic peptides was studied in BALB/c and C57Bl/6 mice. The peptides: (NANP)3 from the Plasmodium falciparum circumsporozoite protein and peptides 136-152 and 205-213 derived from the capsid protein of foot-and-mouth disease virus were coupled to polytuftsin or dituftsin. Anti-peptide IgG titers were determined after two immunizations. All of these three non-immunogenic peptides coupled to polytuftsin or dituftsin induced anti-peptide antibody production in mice while peptides alone did not elicit IgG. In addition, a conjugate of (NANP)3 and polytuftsin with built-in glycopeptide adjuvant elicited an anti-peptide response comparable in magnitude with that of a peptide-KLH conjugate. The data suggest that when non-immunogenic peptides are synthesized in tandem with dituftsin or conjugated to polytuftsin a significant immune response to the peptides may be elicited. This approach may be employed in synthetic vaccine design.

Amino Acid Sequence↗
PubMed2001

[Anticipated and unexpected physiological effects of oligopeptides (glyprolines, ACTH (4-10) analogs, taftsin, and thyroliberin)].

A short review of investigations resulting in determination of a new family of regulatory peptides (glyprolines) participating in modulation of hemostasis and protection of mucous membranes, obtaining of the ACTH4-10 new analogues which are potent neuroprotectors and nootrops, and revealing of unexpected biological activities of some other peptides (behavioural effects of tuftsin, lymph flow stimulation by thyroliberin, etc.). Further investigations into the functional peptide continuum is discussed.

Adjuvants, Immunologic↗
PubMed2002

[Selank and short peptides of Taftsin derivatives in regulation of adaptive behavior of animals in stress].

Effects of 10 peptides, tuftsin and Selank derivatives upon behavior during emotional stress induced by conflict situation, were studied in Balb/c and C57BL/6 male mice with genetically determined opposite types of emotional stress reaction, in white male mice and in Wistar male rats divided into different groups according to the type of emotional reactivity. Positive effects of some peptides upon the adaptive behavior of animals in stress situation were demonstrated. Individual physiologically important effects depending on molecular structure of the peptides under study and/or their fragments, possible products of degradation, were revealed. The results obtained confirm the perspectives of aimed synthesis of peptides with definite pharmacological activity, which are not ksenobiotics and will have no side effects.

Adaptation, Psychological↗
PubMed1989

[Immunostimulants--therapeutic aspects].

A survey is given about the so far known mode of action and the therapeutic application of the following agents with immunostimulatory effects: Interleukin-2, Interferon-gamma, Tumor necrosis factor, Thymosin alpha 1, Thymopentin, Splenopentin, Thymulin, Thymostimulin, Muramyl dipeptide, Bestatin, Tuftsin and Levamisole. The treatment of patients suffering from immunodeficiency disorders and cancer with such agents seems to be possible in the near future.

Acetylmuramyl-Alanyl-Isoglutamine↗