Transfer factor--transfer of tuberculin cutaneous sensitivity in an allogeneic and xenogeneic monkey model.
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Transfer factor derived from lymphocytes of donors with strong cellular immunity against beryllium was intradermally or subcutaneously injected into unprimed or subclinically primed human recipients who were patch test-negative. These recipients were challenged with beryllium at weekly intervals thereafter. Subjects who had been subclinically primed and received transfer factor either intradermally or subcutaneously showed transient patch test reactivity to the challenge. Subjects who received transfer factor but were not primed and subjects who had been primed but did not receive transfer factor showed no such conversion. This is the first demonstration of transfer of contact sensitivity in man using transfer factor, and it suggests that subclinical priming is necessary for such transfers.
A population study was performed to obtain local normal values of the transfer factor for a respiratory laboratory providing a routine hospital service. Statistical analysis of the results obtained showed similar results to those of previous investigators for the transfer factor and alveolar volume. The transfer factor was found to be dependent on height, age and sex, while the alveolar volume depended only upon height and sex. Unlike previous investigations, however, the present study showed that the transfer coefficient was the same for women as for men and was related solely to age.
Transfer Factor (TF) was produced by ultrafiltration of repeatedly frozen and thawed, pooled buffy coats of healthy blood donors. One unit of TF Zürich was defined as the cell extract originating from 1 - 2 x 10-9 leucocytes. In collaboration with physicians and immunologists, 409 units TF have been given to 45 patients. Besides local pain and occasional fever no side effects were observed. Immune conversions and beneficial clinical effects were seen in 11 and 10 patients, respectively, out of 12 patients with chronic candidiasis. Immune conversion was also observed in patients with multiple sclerosis, while the clinical effects cannot yet be judged. The series also included patients with subacute sclerosing panencephalitis, HBAg-positive disorders, various immunodeficiency diseases, malignant malanoma and miscellaneous tumours. Immune conversion occurred only occasionally and the clinical effect was either non-existent or not judgeable. In the discussion the results of other investigators using TF therapy are included.
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Human transfer factor was prepared from "buffy coat" of human donors by ultra filtration. These batches of transfer factor were tested for their ability to increase DNA-synthesis of antigen(mitogen) incubated lymphocytes. An increase of DNA-synthesis was measured by the ratio of appr. 2. Column chromatographic separation of transfer factor on sephadex G-10 or DEAE cellulose columns showed an elution pattern with many peaks. In the lymphoblastogenese assay some peaks were found to be stimulatory, others in contrast inhibitory. It seems likely from our results that transfer factor represents a mixture of different chemical compounds with activating or inhibitory action on lymphoblastogenesis.
Dialyzable transfer factor, obtained from human peripheral blood leukocytes and first described by Lawrence, is being used in attempts to rectify defects in the cellular immune systems of patients with basic immunodeficiencies, chronic infectious diseases, and neoplastic diseases. Current knowledge of the chemical character of, assays for, and functional activities of transfer factor are briefly reviewed. An experimental animal model for dialyzable transfer factor involving the rhesus monkey (Macaca mulatta) and infection with the trematode Schistosoma mansoni is discussed. The results of this study suggest that in this model transfer factor may act both specifically and nonspecifically.
The transfer factor is a tiny molecule capable of transferring the function of the T lymphocytes (immunological memory and retarded hypersensitivity) from a sensitized to a non-sensitized individual. The exact structure and action modalities of the molecule have not yet been precisely established. The difficulties involved in the study of the transfer factor are aggravated by the lack of any suitable experimental model. The attention of immunologists is attracted by this factor which opens up new prospects for the treatment of cancer, immunological deficiencies and certain infectious and autoimmune diseases. More profound research would appear useful to evaluate if and in what cases a potentiation of the immune mechanism can represent an alternative to immunosuppression.
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Three investigations are described in which non-dialysed and dialysed leucocyte lysates, 'transfer factor' prepared from the blood of sheep infected with Trichostrongylus axei successfully transferred immunity to challenge infection with that parasite in susceptible lambs. Similar leucocyte lysates from parasite-free lambs failed to transfer a similar resistance to challenge infection. 'Transfer factor' treatment produced a 30--72 per cent reduction in a total worm burden compared to susceptible control lambs. In the first two investigations the donor and recipient lambs were genetically dissimilar and in the third investigation were of different breeds. The resistance transfer was considered to operate independently of immune incompetence.
Dialyzable transfer factor (dTF) was fractionated on Sephadex G-10 and G-25 fine columns, and biological activity was found in 3 fractions. One of these, designated VIa, and having a tendency to adsorb to the Sephadex G-10 gel, was shown to have a therapeutic effect on certain immunological diseases. Analysis of this fraction on thin-layer and gas chromatography and with infrared and mass spectroscopy indicated that about half of this fraction was composed of uracil; additional unidentified heterocyclic and aromatic substances were present in this fraction. Adjacent fraction V contained tyrosine and a small polyribonucleotide, and fraction VII hypoxanthine and additional unidentified components. Our results suggest that the therapeutic activity of dTF is not mediated through an immunologically specific informational molecule, but is rather based on non-specific stimulation of the expression of the immune response.
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The in vivo and in vitro demonstration of specificity of transfer factor (TF) has so far been hampered by lack of a suitable antigen. The host partiality of Leishmania suggested that in the case of leishmania antigen it should be possible to obtain lymphocytes of both donors and recipients of TF which were either sensitized or truly virgin. Lymphoblast transformation of normal donor lymphocytes to leishmania major antigen (LMA) was therefore measured in the presence of TF prepared from donors with a history of cutaneous leishmania infection (LSTFd) and normal donors (NSTFd). A clear augmentation of the lymphoblast transformation equal to that usually seen when lymphocytes from sensitized individuals are exposed to LMA was observed with LSTFd. An insignificant increase in lymphoblast transformation, however, occurred when NSTFd was used together with LMA and when LSTFd or NSTFd was used alone. The results, although limited by the number of TF preparations, tested, clearly substantiate the in vitro specificity of TF.
Dialyzable transfer factor was prepared from the spleens of CF1 mice actively sensitized with killed Coccidioides immitis antigen. The transfer factor was administered to normal mice either intraperitoneally or into the hind footpads. The recipient mice were tested for reactivity to the coccidioides antigen and to Candida albicans antigen by means of the footpad swelling test. The transfer factor conferred antigen-specific reactivity upon normal recipient mice when given by the intraperitoneal and footpad routes. This capacity of the transfer factor was destroyed by in vitro pretreatment with dimerized ribonuclease A, an enzyme active against double-stranded, as well as single-stranded, ribonucleic acid. In contrast, monomeric ribonuclease A, which is active against only single-stranded ribonucleic acid under the conditions used here, was without effect upon the transfer factor. These data provide evidence that murine transfer factor contains ribonucleotides that are essential for immunological activity. In addition, the data are consistent with the hypothesis, advanced by others, that the ribonucleotides may be double-stranded or uniquely looped configurations.
Transfer factor is a dialyzable extract of sensitized leukocytes, which transfers reactivity from skin test-positive donors to skin test-negative recipients. Transfer factor supplied by our laboratory has been used therapeutically to induce cellular immunity in 78 patients around the world. Many patients received multiple doses of transfer factor ranging from 1 unit given every 6 months for 3 years to 1 unit every week for 6 months to as much as 8 units per week for a brief period. A total of 299 units of transfer factor have been given. Diseases in which transfer factor appeared to cause improvement include the Wiskott-Aldrich syndrome, severe combined immunodeficiency disease, mucocutaneous candidiasis, chronic active hepatitis, coccidioidmycosis, dysgammaglobulinemia, Behcet disease, aphthous stomatitis, linear morphea, familial keratoacanthoma and malignancy.
Transfer factor was first discovered by Lawrence in 1955, but was not used therapeutically until 1969 when we reported its use in a Wiskott-Aldrich patient. Since that time, it has been used in a wide variety of disorders related to defects in cellular immunity, infectious diseases, and malignant diseases. This report describes our experience with transfer factor. Report number I discusses rationale for patient selection, procedures for transfer factor therapy, procedures for monitoring the efficacy of therapy, untoward effects of therapy, and experience with transfer factor therapy in severe combined dual system deficiency disorder. The results of our study on transfer factor therapy indicate that it is capable of inducing a clinically acceptable level of cell-mediated immunity in approximately 50% of patients with a variety of immunodeficiency disorders. It also appears to be a useful adjunct to chemotherapy, and may possibly act synergistically with transplanted fetal thymocytes to produce a constantly regenerating specifically competent source of T lymphocytes, thereby obviating the need for bone marrow transplant for severe combined dual system deficiency disorder.
Dialyzable Lawrence-type transfer factor was prepared from the spleen cells of CF1 mice inoculated with Coccidioides immitis- and Candida albicans-killed vaccines and with live Mycobacterium tuberculosis vaccine (BCG). These preparations were shown to transfer antigen-specific cell-mediated immunity to naive mice, as measured by the delayed skin test and footpad-swelling methods. Reactivity could be demonstrated when the test antigens were given 24 h after the transfer factor, but not when they were given simultaneously. Coccidioides-specific transfer factor was shown to be sensitive to Pronase and resistant to trypsin and ribonuclease. A preparation of BCG transfer factor was sensitive to snake venom phosphodiesterase.