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Episome-mediated transfer of drug resistance in Enterobacteriaceae IV. Interactions between resistance transfer factor and F-factor in Escherichia coli K-12.

Watanabe, T. (Keio University, Tokyo, Japan) and T. Fukasawa. Episome-mediated transfer of drug resistance in Enterobacteriaceae. IV. Interactions between resistance transfer factor and F-factor in Escherichia coli K-12. J. Bacteriol. 83:727-735. 1962. - Resistance transfer factor (RTF) present in F(+) and F'(+) strains was found to suppress completely the transfer of F-factor, F', and host chromosomes. On the other hand, the presence of RTF in Hfr strains was found to reduce the frequencies of recombination to about 10(-2) of those in Hfr strains, regardless of the types of Hfr. RTF present in an F(+) strain with colicinogenic factor E(1) inhibited the transfer of the colicinogenic factor, whereas the transfer of colicinogenic factor I was not suppressed by RTF. A hypothesis that the genetic determinant of RTF controlling its "transfer system" is epistatic to that of F-factor is presented. It was also shown that F-factor present in recipients slightly suppresses the acceptance of RTF and that RTF present in recipients slightly reduces the acceptance of F-factor, F', and host chromosomes. On the other hand, the acceptance of RTF by recipients in which RTF is present was found to be about 1% of that in recipients without RTF.

Drug Resistance↗

Transfer factor for the treatment of HBsAg-positive chronic active hepatitis.

Transfer factor was obtained from four patients having recovered from acute type-B viral hepatitis. It was replicated in vitro using the LDV/7 lymphoblastoid cell line. This in vitro-produced transfer factor specific for hepatitis B (TFdL-H) was administered to 10 randomly selected patients with biochemically and histologically proven HBsAg-positive chronic active hepatitis (CAH) at 15-day intervals over a 6-month period. In three out of four initially HBeAg-positive patients, anti-HBe antibodies appeared when the HBeAg disappeared. In one of these patients and in two other HBsAg-positive patients, the appearance of anti-HBs antibodies was noted. The improvement in several biochemical parameters of the TFdL-H patients was statistically significant when compared with those of another group of 10 randomly selected untreated CAH patients. Liver biopsies in six out of eight treated patients showed a histological improvement at the end of the treatment. These results suggest that TFdL-H may be used with beneficial effect for the treatment of HBsAg-positive CAH.

Adult↗

Transfer factor - hypotheses for its structure and function.

Transfer factor (TF) is a dialyzable extract from primed lymphocytes that is able to transfer specific delayed hypersensitivity from one animal to another. On the basis of available data we suggest that TF is a polypeptide with a molecular weight below 15,000 daltons. We hypothesize that TF is the variable light or heavy chain domain of immunoglobulin: such a molecule conforms with the accepted properties of TF and also has the necessary specificity requirements. We also hypothesize that TF is part of a receptor site. beta-2-microglobulin, a molecule that is an integral part of cell surfaces, could be the anchor for TF. beta-2-microglobulin has homologies with the constant portion of immunoglobulin light or heavy chain and thus would combine with the variable domain (TF) to form a complete receptor site for a specific antigen. The properties of TF suggest its mode of action, which is discussed in detail in the text. The biologic advantages of TF is its ability to confer immediate (immunologie specific) protection while the 'normal' immune response develops.

Binding Sites, Antibody↗

Failure of transfer factor therapy in atopic dermatitis.

A controlled clinical study was conducted on 6 patients with atopic dermatitis to assess the efficacy of transfer factor. After the code was broken the 3 patients treated with placebo preparation were treated with transfer factor for a further period of 10 weeks. No definite therapeutic effects could be demonstrated. The immunological in vivo and in vitro tests failed to reveal any effects except for a change to positive in the tuberculin skin test in those patients who had previously been skin test negative. The treatment had to be discontinued in one patient due to a suspected allergic reaction against transfer factor.

Adult↗

[Therapy with transfer factor in diseases with disorders of the cellular immune reaction].

On the basis of publications on experimental therapy with transfer factor is tried to show limits and perspective of a new therapeutic principle. The now 10-year-old therapeutic experiences with dialysates of leucocytes and chromatographically cleansed fractions were confirmed by the new investigations of the last years which were evaluated. They show the transfer factor as an effective immune therapeutic for the stimulation of the cellular immunity in a large number of diseases. In these cases a combination with other therapeutic measures proved particularly favourable. Concerning the breadth of use and the chances of success chronic infections are in the foreground. A practical importance of the transfer factor for the treatment of malignant diseases is at present not to be seen. Comprehensive double blind studies with large groups of patients are further necessary, in order to exclude accidental findings for the corresponding picture of the disease and to estimate possible chances of success.

Humans↗

Passive transfer of immunity to trichostrongyle species infections in sheep. Investigations of specificity and limitations of 'transfer factor' activity with Trichostrongylus axei infections.

The ability of transfer factor (TF) preparations to transfer resistance to challenge with Trichostrongylus axei in sheep and to correct partially the immune immaturity of young lambs was confirmed. Non-dialysed TF consistently transferred resistance but dialysed TF frequently failed, perhaps demonstrating a loss of activity during TF preparation procedures. Specificity of transfer was demonstrated when T. axei TF transferred resistance to T. axei challenge but Haemonchus contortus TF failed to do so.

Animals↗

Clinical and immunological improvement in a patient with chronic mucocutaneous candidiasis treated with transfer factor.

In a 19 year old patient suffering from CMC since the first months of life, clinical improvement accompanied by correction of the immunologic defect was achieved by Transfer Factor therapy. After 12 months from the last administration of Transfer Factor the improvement persisted. The positive outcome of the treatment in this disease is not constant. Possibly only patients with cellular immunologic defects are susceptible of a favourable response, moreover it is thinkable that the quality of Transfer Factor and the dosage administered must play a role.

Adult↗

Transfer factor therapy in multiple sclerosis: a three-year prospective double-blind clinical trial.

One hundred five patients with MS were divided into three groups matched for age, sex, and disability, and treated with either placebo, transfer factor prepared from leukocytes of random donors, or transfer factor from leukocytes of family members living with the patients. There were no differences in the three treatment groups for changes in disability, activities of daily living, or evoked potentials. Eighteen months of transfer factor therapy had no effect on gamma-interferon production or natural killer cell activities.

Activities of Daily Living↗

Transfer factor is ineffective in amyotrophic lateral sclerosis.

Sixty-six patients with amyotrophic lateral sclerosis (ALS) participated in a double-blind, placebo-controlled study of transfer factor. A structured rating score of neurological function was recorded after each monthly administration of transfer factor or placebo. Statistical analysis of mean scores for all patients and for those with specific clinical abnormalities showed no significant difference between the two groups. There was no evidence of therapeutic value for transfer factor. During the observation period of nearly one year, more than two-thirds of the deterioration occurred in the first six months. Meaningful clinical trials of other potential therapeutic agents could probably be conducted within six months in double-blind crossover trials.

Adult↗

Transfer factor (diffusing capacity) standardized for alveolar volume: validation, reference values and applications of a new linear model to replace KCO (TL/VA)

Transfer factor (TL) varies with alveolar volume (VA), but not in the manner implied by the carbon monoxide transfer coefficient (KCO (TL/VA)). This paper considers two other simple models (one linear and one exponential) which might standardize TL for VA, and asks the questions: 1) Is either model valid? 2) What are appropriate reference values? and 3) Will the model be useful? The relationship of TL to VA within subjects at different depths of inspiration, and between subjects having lungs of different sizes, were measured and compared. The subjects were asymptomatic, nonsmoking, Caucasian adults, including 31 males assessed in the laboratory and 503 male and female participants in population studies. The linear partial regression coefficients of TL on VA (L corrected for body temperature, atmospheric pressure and water saturation (BTPS)) standardized for height (H) in metres, were similar within- and between-subjects; the coefficients applied over a wide range of values for VA. This was not the case for the exponential model. The resulting reference equations in SI units for males and females were: TL = 11.52 H + 2.72 VA.H-2 - 0.051 Age -12.35. RSD 1.17; and TL = 4.87 H + 2.29 VA.H-2 - 0.019 Age -3.03. RSD 0.92, respectively. The residual standard deviations (RSD) about the new relationships were less than in other series. The new linear model could account for much of the variation between different published reference values for TL; it could be useful clinically, in circumstances when VA deviates from the norm. The model does not explain differences in TL associated with gender. Inclusion of VA.H-2 as a covariate in the reference equation for transfer factor, in addition to age and height, improves the accuracy of prediction of normal transfer factor compared with current reference values; its use suggests that some of the differences between published values is due to the volume term. The equations can be used clinically, and eliminate the need for carbon monoxide transfer coefficient.

Adult↗

Human transfer factor prepared by dialysis, ultrafiltration and gel chromatography: biological activity in local transfer of skin sensitivity.

Human transfer factor (TF) was prepared by a variety of methods including dialysis using cellophane tubing, ultrafiltration through a membrane of known pore size. Sephadex G25 chromatography or combinations of some of these methods. In general the various preparations when injected locally into human skin gave greater delayed-type responses than antigen (PPD or Candida) alone. The combination of either vacuum dialysis, or ultrafiltration, with G-25 chromatography gave as good or better TF activity when compared with unchromatographed materials. Since ultrafiltration and concentration is rapid procedure and eliminates the need for freeze-drying, in contrast to vacuum dialysis against water, these results indicate that ultrafiltration and G-25 chromatography provide a convenient method for preparing large batches of relatively pure TF from leucocyte extracts.

Antigens, Fungal↗

Dialyzable transfer factor in the treatment of human osteosarcoma: an analytic review.

In conclusion, then, we would answer the seven questions raised earlier concerning transfer factor as follows: Certianly, as shown by clinical results, it does exist. It does have a definite immunologic effect in humans, boosting cell-mediated immunity, as shown by a rise in the level of active T cells. Its clinical effects have been demonstrated repeatedly, and it should become useful in still other clinical situations as further research provides more effective therapeutic modalities. Transfer factor from selected donors appears to provide prophylaxis against metastasis when administered to osteosarcoma patients with no clinically evident metastases at the time of surgical removal of the primary tumor; whether this treatment is superior to chemotherapeutic prophylaxis is conjectural and controversial. Its mechanism of action has not been demonstrated as yet, although many theories exist. The best evidence is that the effects are both specific and nonspecific. It appears to be produced by T lymphocytes. The exact nature of the substance we call "transfer factor" remains to be elucidated. Further research should provide more conclusive answers to these questions.

Animals↗

Immunocompetence and transfer factor therapy in uveitis.

A study of the clinical course of 20 patients with uveitis treated with transfer factor is reported. Twelve (60%) of the patients were initially immunoincompetent on screening. Eight of the 12 changed to an immunocompetent status after treatment and could either decrease or discontinue their anti-inflammatory drugs. Five had a statistically significant improvement in visual acuity. One of the 8 initially immunocompetent patients had a statistically significant visual improvement, and 2 decreased or discontinued all drugs, while 3 increased their drugs.

Adolescent↗

In vitro determination of effects of dialyzable leukocyte extracts containing transfer factor activity.

The studies for determining the effects of dialyzable leukocyte extracts (transfer factor) as reflected in recovery of E-rosetting capacity in trypsinised lymphocytes (recovery-assay) suggested the following: 1. Dialyzable leukocyte extracts contain an inhibitor with a molecular weight of about 5000 (fraction I). 2. This inhibitor considerably affects the immunologic activity of both whole preparations and their different fractions during the in vitro activity assay. 3. The inhibitor fraction that fails to respond to the "recovery-assay" (less than 5%) responds very actively to the test after inactivation (45 min/57 degrees C). 4. Therefore, activation assays performed on the total preparation after inactivation involve a considerable error. 5. Immunological activity is concentrated in fractions III and IV. Only fraction III activity can be reduced considerably by inactivation. Fraction II activity is induced by incomplete separation from fraction III. Fraction IV cannot be inactivated. 6. In the case of transfer factor preparations (without inhibitor fractions) activity increases almost in direct proportion to the concentration up to about 30 micrograms. 7. Since the "recovery-assay" also responds to substances with no immunologic activity, its use can be justified in the case of fraction III. The activity is then the difference between the native and the inactivated forms. 8. A corresponding review of methods (such as LTT, migration inhibition test, skin test, etc.) currently used for activity assays seems advisable.

Chromatography, Gel↗

The relationship between the transfer factor obtained at rest, and arterial oxygen tension during exercise, in patients with miscellaneous pulmonary diseases.

Forty-one consecutive patients with the symptom 'exertional dyspnoea' were referred to the Department of Clinical Physiology for evaluation. Pulmonary fibrosis and chronic obstructive pulmonary disease were the most common diagnoses but other diagnoses were also represented. Some patients had no clinical diagnosis or radiological signs. All patients underwent exercise testing with sampling of arterial blood for blood gas analysis and pulmonary function testing including measurement of the transfer factor (carbon monoxide diffusing capacity) at rest. Independent of spirometric findings and diagnosis a significant correlation (r = 0.80, P < 0.001) was shown to exist between the transfer factor measured at rest and the arterial oxygen tension at maximal exercise level. We recommend measurement of the transfer factor as a screening test for exertional hypoxaemia and suggest that exercise blood gas analysis only seems necessary in patients with a transfer factor between 55% and 80% of the predicted value.

Adult↗

Leukocyte migration inhibition of buffy coats from patients with autoimmune thrombocytopenic purpura when exposed to normal platelets: modulation by transfer factor.

Cellular-mediated immunity was studied in autoimmune thrombocytopenic purpura (ATP) patients by investigating leukocyte migration inhibition (LMI) following the interaction of normal platelets with patients' lymphocytes. When normal platelets were incubated with leukocyte buffy coats of ATP patients, the migration index (MI) was significantly impaired compared to buffy coats from normal subjects, employing 4 different concentrations of platelets. At the highest platelet concentration (10(9)/ml), MI was 0.87 +/- 0.04 (SEM) for ATP lymphocytes compared to 1.05 +/- 0.05 (p less than 0.01) for normal lymphocytes. Nine of 21 patients had an MI less than 0.80, whereas all control subjects had MIs greater than 0.85. Similar results were obtained at 2 different platelet membrane concentrations. At 500 micrograms/ml, the MI for ATP lymphocytes was 0.74 +/- 0.04, compared to 0.98 +/- 0.08 (p less than 0.01) for normal lymphocytes (12 experiments). An inverse relationship was noted between platelet count and lymphokine production in ATP patients (r = 0.815, p less than 0.001, 10 experiments). Transfer factor from an ATP patient in remission converted an abnormal LMI response of 0.68 +/- 0.04 from a patient with severe thrombocytopenia to 0.84 +/- 0.07 (p less than 0.005, 8 experiments). Similar results were obtained with transfer factor from 2 other patients in remission. Transfer factor from a patient with severe thrombocytopenia converted a normal response of 1.04 +/- 0.05 of normal subjects to a lower response of 0.88 +/- 0.04 (p less than 0.03, 12 experiments). Thus, lymphocytes of ATP patients are primed to recognize and be perturbed by normal platelets, whereas normal lymphocytes are not. This indicates specificity of the antigen-lymphocyte reaction in ATP patients. Transfer factor is capable of modulating this response in vitro.

Adult↗

Chronic mucocutaneous candidiasis treated with transfer factor.

A patient with chronic mucocutaneous candidiasis resistant to all tropical therapy has had extensive tests of immunological function carried out before and after administration of transfer factor. Immunological testing has been both specific, directed at responses to candida antigen, and non-specific, directed at general assessment of the patient's immune status. Transfer factor has been administered on three occasions in the past year. After each treatment temporary clinical improvement accompanied by changes in both specific and non-specific immunological responses have been observed. The possible mode of action of transfer factor in this case is discussed.

Adult↗

[Human transfer factor. I. Production by the great pool technic and the biochemical and immunological characteristics of the preparation].

A great pool procedure for producing human transfer factor preparations from buffy-coats of stored whole blood which has not been used up till now is described. From an initial tool size of about 1,500 units of whole blood the procedure represented makes it possible to gain higher amounts of uniform and in their immunological efficacy in vitro standardizable preparations for controlled long-term therapy studies. By means of various immunological in vitro tests, stimulating as well as suppressing activities of the charges obtained could be identified. Starting from the differentiated immunological effects of various charges of the transfer factor on T-cell populations in vitro, the possibility of influencing T-cell subpopulations through well-conceived therapeutic measures by a transfer factor is discussed.

Adult↗