[Transfer factors in medical therapy]. / Factores de transferencia en la terapéutica médica.

Transfer factor (TF) consists of messenger peptides produced by activated T lymphocytes as part of cellular immunity, and it acts in virgin lymphocytes through TF inducers, suppressors and specific antigens. TF is not immunogenic because it is not species-specific, since it contains a consensus sequence of amino acids LLYAQDL/VEDN. TF extracted from leukocytes can transfer immunity from a human to another species. TF extracts are complex, containing more than 200 molecules with molecular weights ranging from 1 to 20 kDa. The antigen specific transfer factors (STF) have molecular weights between 3,5 and 5 kDa. TF is easy to prepare and well tolerated. It does not contain HL-A antigens against potential receptors and it can used as adjuvant therapy in several diseases.

Serial lung function tests in primary immune deficiency.

Pulmonary complications are common in patients with primary immune deficiency (PID). The aim of this study was to assess the usefulness of lung function tests (LFTs) in the management of these patients, and in particular to see if carbon monoxide transfer factor (TLCO) is needed in addition to spirometry. We studied 20 patients (11 female) with PID in a tertiary referral clinic, with a mean age of 47.6 years. Serial LFTs, spanning a mean of 101 months, were correlated with immunoglobulin levels and antibiotic usage. Seven patients showed a decline in forced expiratory volume in 1 second over the period of the study. An additional five patients showed a decline in TLCO. Of these 12 patients, two had no radiographic evidence of lung disease. Higher levels of immunoglobulin were associated with slower decline in LFTs (P < 0.05). The analysis of antibiotic usage and LFTs failed to show a statistically significant effect, although there was a trend towards a slower rate of decline with greater use of antibiotics. LFTs decline slowly in patients with PID. Annual testing (both spirometry and transfer factor) is useful in the assessment of these patients, and should not be confined to those with radiological evidence of lung disease.

Transfer of selected elements from food into human milk.

OBJECTIVES: We measured the transfer factors of antimony, cerium, chromium, cobalt, gallium, lanthanum, molybdenum, niobium, ruthenium, silver, thorium, titanium, and uranium from food to milk in nursing mothers. METHODS: Food and milk samples from 19 mothers were taken daily over 2 to 8 wk. The samples were analyzed for element content after microwave-assisted pressure digestion with a mass spectrometer and inductively coupled plasma. The transfer factor, or the portion of element intake passed on in the milk, was calculated as the element concentration in food (g/kg) divided by the element concentration in milk (g/L). RESULTS: The calculated transfer factors were 5.1 for silver, 16.1 for cerium, 6.9 for chromium, 8.4 for cobalt, 19.1 for gallium, 13.8 for lanthanum, 77.4 for molybdenum, 20.7 for niobium, 4.1 for ruthenium, 13.2 for antimony, 20.2 for thorium, 5.6 for titanium, and 21.3 for uranium. Factors differed significantly across individuals. CONCLUSION: These differences can be attributed to the fact that the different levels of elements in breast milk are the result of individual differences in milk production and factors other than the amount of any particular element absorbed by the body.

Longitudinal changes in physiological, radiological, and health status measurements in alpha(1)-antitrypsin deficiency and factors associated with decline.

The FEV(1) declines rapidly in alpha(1)-antitrypsin deficiency (alpha(1)-ATD) but less is known about other measures of disease severity and the factors, other than smoking, that are associated with progression of emphysema. The natural history of alpha(1)-ATD was studied prospectively in 43 patients with the PiZ phenotype and emphysema at a single center over 2 yr. The mean +/- SE change in FEV(1) was -67 +/- 14 ml/yr, accompanied by a reduction in transfer factor (mean change in diffusing capacity of the lung for CO [DL(CO)] -1.07 +/- 0.21 ml/min/mm Hg/yr; p < 0.001) and lung density in the upper zones as assessed by quantitative high-resolution computed tomography (HRCT) (mean change in voxel index 2.8 +/- 0.6%/yr; p < 0.001). The decline in FEV(1) related to baseline FEV(1) (r = -0.56, p < 0.001), bronchodilator reversibility (r = 0.52, p < 0.001), and (for patients with FEV(1) > 35% predicted) exacerbation frequency (r = -0.38, p = 0.02). There was also a decline in the St. George's Respiratory Questionnaire (SGRQ) Activity score (mean change -4.3 +/- 1.2 units/yr, p < 0.001) that correlated with FEV(1) decline (r = 0.45, p = 0.002). Progression of emphysema in alpha(1)-ATD is dependent on baseline physiology and exacerbation frequency and may be detected by several different measurements of which HRCT density mask analysis and DL(CO) appear most sensitive.

Transfer factor--current status and future prospects.

We have detected new clues to the composition and function of "Transfer Factor" using the direct Leucocyte Migration Inhibition (LMI) test as an in vitro assay of Dialysates of Leucocyte Extracts (DLE). This approach has revealed two opposing antigen-specific activities to be present in the same > 3500 < 12,000 DA dialysis fraction - one activity is possessed of Inducer/Helper function (Inducer Factor). The opposing activity is possessed of Suppressor function (Suppressor Factor). When non-immune leucocyte populations are cultured with Inducer Factor they acquire the capacity to respond to specific antigen and inhibition of migration occurs. This conversion to reactivity is antigen-specific and dose-dependent. When immune leucocyte populations are cultured with Suppressor Factor their response to specific antigen is blocked and Inhibition of Migration is prevented.

Structural nature and functions of transfer factors.

Transfer factors are molecules that "educate" recipients to express cell-mediated immunity. This effect is antigen-specific. The most consistent effects of transfer factors on the immune system are expression of delayed-type hypersensitivity and production of lymphokines such as macrophage migration inhibitory factor (MIF), which is probably identical to gamma-interferon in response to exposure to antigen. Transfer factors bind to antigens in an immunologically specific manner. This discovery has enabled us to isolate individual transfer factors from mixtures that contain several transfer factors. This reactivity probably explains the specificity of individual transfer factors, and it has provided a method for purification of individual transfer factors to apparent homogeneity. The purified materials are immunologically active and antigen-specific. They have molecular weights of approximately 5,000 Da and appear to be composed entirely of amino acids. Transfer factors appear to offer a novel means of molecular immunotherapy for certain patients with defective cell-mediated immunity.

Transfer factor and its signification for practice.

In the study literary data are given together with our own experience with the immunomodulation effects of Transfer Factor (TF) Sevac. The application of 3-5 ampulles of TF leads not only to E rosettes but even to a separate subpopulations of T lymphocytes increase. The results obtained in 51 patients with GIT and renal cells carcinoma were statistically evaluated. About 80% of the patients experienced an improvement of subjective conditions during the treatment. Objectively supported adjustment of laboratory indices was found in 83-88% of the parameters evaluated. Also the absolute numbers of CD4+ cells in 10(9)/1 increased (at p < 0.001) together with CD3+ and CD8+ (p < 0.01). A significant correlation between separate subpopulations of T lymphocytes and B lymphocytes was proved in the original mode. From our results it is obvious that the TF Sevac application and further observing of its immunomodulation effect will be the object of interest of the immunologists of general practice and clinical research even in spite of some lacks in its characteristics.

Lung function in primary Sjögren's syndrome: a cross sectional and longitudinal study.

Clinical and radiological assessment of 100 patients (97 female) with primary Sjögren's syndrome was performed within six months of diagnosis in conjunction with spirometry and measurement of transfer factor for carbon monoxide (TLCO). This was repeated in an unselected subgroup of 30 patients after a mean interval of four years. On initial assessment, 43 patients had symptoms of lung disease and 10 had related physical signs; the chest radiograph was abnormal in five. There was a significant reduction (more than 2 standardised residuals) in forced expiratory volume in one second (FEV1), vital capacity (VC), and TLCO in 14, 12, and 10 patients, 24 patients overall having a significant reduction in one or more of these measures. There was a strong relation between reduction in lung function and both pulmonary symptoms and a lip biopsy specimen positive for Sjögren's syndrome. Lung function at the initial assessment in the 30 patients who were restudied was almost identical to that of the group as a whole. Seventeen now had symptoms and nine had related physical signs. The chest radiograph was abnormal in four patients. More patients had a significant reduction in FEV1, VC, and TLCO. Lung disease is sometimes an early feature of primary Sjögren's syndrome and may progress over a relatively short period.

Biological response modifiers. Interferons, interleukins, and transfer factor.

Natural consequences of knowledge of the mechanisms that regulate immune responses are the attempts to modify the immune system in order to increase resistance to infectious diseases and to enhance activity against tumor cells. This review describes the roles of interferons and interleukins in immune responses and reviews the experience with transfer factor in treatment of certain diseases.

Counter inhibitor: a low molecular weight cytokine derived from human leukocyte dialysates reverses antigen dependent PMN and macrophage migration inhibition.

A low molecular weight component, termed counter inhibitor (CI), has been partially purified from human dialyzable leukocyte extracts. Addition of CI to either a direct leukocyte or macrophage migration inhibition system results in reversal of antigen-induced migration inhibition. CI activity requires the presence of antigen for expression, but does not require that the donor of the CI be immune to the antigen used in the migration inhibition assay. Reversal of migration inhibition by CI appears to be a consequence of its ability to prevent PMNs or macrophages from responding to lymphokines which induce migration inhibition.

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.

Transfer factor.

A workshop on transfer factor, sponsored by the Immunology, Allergic and Immunologic Diseases Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, was held in Bethesda, Maryland, on February 25, 1981. The purpose of the meeting was two-fold: (1) to review the state of the art of transfer factor and (2) to suggest future directions for research in this area, specifically in regard to the prophylactic use of transfer factor for varicella-zoster in leukemic children.

Effects of dialyzable leukocyte extracts with transfer factor activity on leukocyte migration in vitro. 1. Antigen-dependent inhibition and antigen-independent inhibition and enhancement of migration.

The effects of DLE containing TFd activity from immune human donors on PBL, obtained from individuals nonresponsive to either PPD or Cocci antigen, were evaluated in vitro by the agarose LMl technique. Several different preparations of DLE were employed to evaluate the specificity and reproducibility of the effects: (1) from donors skin test positive to PPD but negative to Cocci, (2) from donors skin test negative to PPD but positive to Cocci, (3) from donors skin test positive to both antigens, and (4) from donors skin test negative to both antigens. With PBL from other human donors used as target cells in the direct agarose LMi technique, three types of effects were demonstrated for all preparations of DLE: (1) antigen-dependent specific LMl, (2) antigen-independent or nonspecific LMl, and (3) antigen-independent enhancement of migration. The demonstration of each activity was found to depend on the concentration of DLE used and the time allowed for migration. In experiments employing purified PMN and MNL as target cells and a two-step indirect LMl assay, it was shown that the antigen-independent effects resulted from the direct of components in DLE on PMN. The antigen-independent inhibition was shown not to result from toxic effects of DLE. It was produced by DLE but not by dialyzable liver or skin extracts when tested using an amount equivalent to DLE as judged by the absorbance at 260 and 280 nm. The antigen-dependent LMl was found to require secretion of a soluble mediator of molecular weight near 69,000, believed to be LMl. Our results indicate that the agarose LMl technique is a useful in vitro assay for studies of the mechanism of action of components in DLE which can specifically convert nonimmune lymphocytes to a measurable antigen-sensitive state (i.e., transfer factor). The antigen-independent effects of DLE may be responsible in part for previously reported nonspecific beneficial effects of DLE when used in immunotherapy.

Effects of dialyzable leukocyte extracts with transfer factor activity on leukocyte migration in vitro. II. Separation and partial characterization of the components in DLE producing antigen-dependent and antigen-independent effects.

Previous studies have shown that DLEs with TFd activity produce both Ag-dependent specific effects (mediated by TFd) and Ag-independent effects on CMl as demonstrated in vitro by agarose LMl. In the present study, Sephadex G-25 gel filtration provided a simple method for separating the DLE components responsible for each effect into distinct fractions. Ag-independent LMl was produced predominantly by Sephadex fraction l, of MW greater than 5000. The active components, further purified on Bio-Gel P-10, were shown to be of MW 14,000 to 17,000 and to contain both polypeptide and ribonucliotide material. The Ag-independent LMl activity was stable to heating at 56 degrees C for 30 min but was partially destroyed at 80 degrees C for 30 min, and the responsible components were shown to act on PMN directly. Ag-independent ELM was produced exclusively by material in Sephadex G-25 fraction V and also acted directly on PMN, whereas the Ag-dependent specific LMl activity was found predominantly in fraction lVb and to a lesser extent in fraction V and could not be detected in a direct assay using only PMN. In addition, a new activity, designated "Ag-dependent ELM activity," which caused increased migration in the presence of Ag, was found in Sephadex fraction lVa. This latter activity might mask the Ag-dependent LMl activity in fraciton lVb. Bio-Gel P-2 chromatography separated the components producing Ag-dependent and Ag-independent effects in fraction V into two separate subfractions (Va and Vb) of MW 1100 to 2000 and less than 900. The activity in fraction lVb eluted at a position identical to that of the components in fraction Va on Bio-Gel P-2. Fractions Va and Vb contained both polypeptide and ribonucleotide material. The Ag-dependent specific LMl or TFd activity was found to be partially inactivated at 56 degrees C and completely destroyed at 80 degrees C. The components responsible for this TFd activity were further purified by HPLC on ODS resin. The TFd activity was mediated by components with retention times much greater than that of adenosine 3'-monophosphate. The active fraction was composed of both polypeptide and ribonucleotide material but did not contain deoxyribonucleotides.