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Transfer factor (TF) is a low-molecular-weight lymphocyte extract capable of transferring antigen-specific cell-mediated immunity (CMI) to T lymphocytes. It has been used successfully as an adjuvant or primary therapy for viral, parasitic, fungal, and some bacterial infections, as well as immunodeficiencies, neoplasias, allergies and autoimmune diseases. From the list of infections that seem to respond noticeably to transfer factor, those due to viruses of the herpes family are particularly remarkable. Indeed, for these viruses it was shown that TF can prevent infection or relapse, acting as a CMI vaccine. Data also suggest its possible use for adjuvant treatment and probably prevention of two currently widespread infections: tuberculosis and AIDS. Furthermore, TF has an interesting potential: answering the challenge from unknown pathogenic agents, a black box effect permitting production of antigen-specific TF to a new pathogen, even before its identification. It thus seems that the preventative potential of transfer factor is as important as its therapeutic one, both discussed in this review.

Ubiquinones (coenzyme Qs (CoQ)) are essential for oxidative phosphorylation in yeasts and humans, although the isomers present in each are different. The human coenzyme Q, CoQ10, is administered orally for the treatment of heart disease and other disorders. Some patients, however, require much higher doses than others to attain a therapeutic CoQ10 blood level. We propose that one possible explanation for this variability is Candida colonization of the GI tract. Many common medical treatments including antibiotics and anti-hyperchlorhydric agents increase the risk of GI tract Candida colonization. Subsequent uptake and utilization of supplemental CoQ10 by the yeast could diminish availability for the human subject. Data from one patient and an in vitro pilot study using two pathogenic strains of C. albicans support this hypothesis. If C. albicans in the GI tract can hinder availability and interfere with therapeutic effects of CoQ10, it could be of clinical significance for large numbers of patients., (Copyright 2001 Harcourt Publishers Ltd.)

40 infantile autistic patients were studied. They ranged from 6 years to 15 years of age at entry. 22 were cases of classical infantile autism; whereas 18 lacked one or more clinical defects associated with infantile autism ("pseudo-autism"). Of the 22 with classic autism, 21 responded to transfer factor (TF) treatment by gaining at least 2 points in symptoms severity score average (SSSA); and 10 became normal in that they were main-streamed in school and clinical characteristics were fully normalized. Of the 18 remaining, 4 responded to TF, some to other therapies. After cessation of TF therapy, 5 in the autistic group and 3 of the pseudo-autistic group regressed, but they did not drop as low as baseline levels.

Twenty five HIV-1-infected patients, at various stages (CDC II, III and IV) were treated orally with HIV-1-specific transfer factor (TF) for periods varying from 60 to 1870 days. All patients were receiving antiviral treatments in association with TF. The number of lymphocytes, CD4 and CD8 subsets were followed and showed no statistically significant variations. In 11/25 patients the number of lymphocytes increased, whilst in 11/25 decreased; similarly an increase of the CD4 lymphocytes was observed in 11/25 patients and of the CD8 lymphocytes in 15/25. Clinical improvement or a stabilized clinical condition was noticed in 20/25 patients, whilst a deterioration was seen in 5/25. In 12/14 anergic patients, daily TF administration restored delayed type hypersensitivity to recall antigens within 60 days. These preliminary observations suggest that oral HIV-specific TF administration, in association with antiviral drugs, is well tolerated and seems beneficial to AIDS patients, thus warranting further investigation.

Transfer Factor (TF) was used in a placebo controlled pilot study of 20 patients with chronic fatigue syndrome (CFS). Efficacy of the treatment was evaluated by clinical monitoring and testing for antibodies to Epstein-Barr virus (EBV) and human herpes virus-6 (HHV-6). Of the 20 patients in the placebo-controlled trial, improvement was observed in 12 patients, generally within 3-6 weeks of beginning treatment. Herpes virus serology seldom correlated with clinical response. This study provided experience with oral TF, useful in designing a larger placebo-controlled clinical trial.

The noncytotoxic immunosuppressive substance detected in crude extracellular products of Streptococcus intermedius (CEP-SI) was fractionated by two steps of preparative isoelectric focusing in sucrose gradients using ampholytes of pH range from 3.5 to 6 and 4 to 5, respectively. The in vitro and in vivo suppressor effects of the most highly purified fraction of CEP-Si, designated fraction 3' (F3'EP-Si), corresponded well with those of the original CEP-Si. F3'EP-Si was sensitive to the effects of alpha, gamma, and delta chymotrypsin, trypsin, and heating. It contained approximately 1% of the total amount of protein found in the original CEP-Si, corresponding to a single band on analytical isoelectric focusing, stainable by Coomassie Blue and of isoelectric point of 4.25. The absorption spectrum of F3'EP-Si had a maximum at 260 nm but its biological activity was resistant to deoxyribonuclease and ribonuclease A and it did not contain material stainable by methylene blue. It was also resistant to neuraminidase and did not contain material stainable by periodic acid schiff. We conclude that the substance responsible for the suppressor activity of CEP-Si is a protein of molecular weight approximately 90,000, which adheres to Sephadex of cellulose acetate and forms complexes with other, nonactive constituents of CEP-Si.

We have studied two patients with common variable immunodeficiency (CVID), impaired cell-mediated immunity, and high percentages of monocytes in their peripheral blood. Removal of monocytes from cultures of peripheral blood mononuclear cells from both patients increased the in vitro responses to phytohaemagglutinin (PHA) and concanavalin A (Con A) but not to purified protein derivative (PPD), as measured by [3H]thymidine uptake. Similarly, supernatants of monocyte cultures from both patients, unlike supernatants of normal monocytes, suppressed the in vitro responses to PHA and Con A but enhanced the response to PPD by cultured mononuclear cells from the patients and from normal donors. Addition of unfractionated mononuclear cells from both patients to normal mononuclear cells suppressed both pokeweed mitogen (PWM) stimulation and IgG production; this effect was abrogated by removal of monocytes from the patients' mononuclear cell populations. This effect of thymosin on both patients' mononuclear cells was assayed in vitro. Thymosin was ineffective in vitro with cells from the first patient; for the other patient, [3H]thymidine uptake by mononuclear cells stimulated with PPD increased, whereas uptake by Con A-stimulated cells decreased, as did the percentage of E rosette-forming cells, providing further evidence of heterogeneity of the CVID syndrome. The effects of thymosin were also dependent on monocytes.

The role of autologous rosette forming cells (ARFC) in humoral immune responses was studied using an in vitro system. While depletion of ARFCs from PBL resulted in a significant increase of either total IgG or anti-TT IgG, addition of these cells to the system decreased the production of immunoglobulin to a level comparable to that of unfractionated PBL. The majority of the ARFCs reacted with anti-Leu2a and anti-Leu8. In contrast, the majority of non-ARFCs reacted with Leu3a and only 10% with Leu8 monoclonal antibodies. Stimulation of unfractionated PBL with concanavalin A (ConA) resulted in an increase of the ARFC population. ConA stimulation also increased the number of cells reactive with anti-Leu2 and/or anti-Leu8. The autorosette population had a higher purine nucleoside phosphorylase (PNP) content than the non-ARFC population. Although the ARFC suppressed synthesis of antibody by B cell in vitro when they were mixed with either autologous or allogeneic B cells, a marked proliferation of non-B cells was evident. We conclude that at least two different subpopulations of T cells are capable of forming rosettes with autologous red blood cells.

Gm, A2m, and Km allotypic markers were examined in 52 Dutch patients with nonseminoma testicular cancer. The distribution pattern of the immunoglobulin allotypes in different groups of patients, classified according to histological diagnosis, did not differ significantly from that in the normal population. These results indicate no relationship between nonseminoma testicular cancer and immunoglobulin allotypes.

Immunoglobulin E (IgE) levels and antisperm antibody titers were determined in samples of serum and seminal plasma from 25 fertile men (Group A), 18 infertile men without measurable immunity to sperm (Group B), and 42 infertile men autoimmune to sperm (Group C), and in samples of serum and cervical and vaginal secretions from 25 fertile women (Group D), 28 infertile women without measurable immunity to sperm (Group E), and 32 infertile women isoimmune to sperm (Group F). Among the men, IgE levels in the serum, measured in international units per milliliter, were elevated in Group C (230 +/- 41, mean +/- SEM) as compared with Groups B (94 +/- 33, P less than 0.05) and A (55 +/- 8, P less than 0.001). In contrast, IgE levels in the seminal plasma in Group C (180 +/- 44) were not significantly different from those in Group B (48 +/- 21), but were higher than those in Group A (8 +/- 2, P less than 0.05). In the women, serum IgE levels were higher (P less than 0.001) in Group F, with isoimmunity to sperm (472 +/- 55), than in Groups E (219 +/- 32) and D (76 +/- 16). Wives of autoimmune husbands had somewhat, though not significantly, higher serum IgE levels (406 +/- 55), than had wives of nonautoimmune husbands (247 +/- 97). These results provide evidence for an elevated IgE response in subjects with significantly elevated antisperm antibody titers.

A "new" polyclonal activator of human peripheral blood B cells, formaldehyde-fixed Salmonella paratyphi B, is described. This bacterium does not stimulate cell proliferation as measured by incorporation of tritiated thymidine but does stimulate a subpopulation of B cells to secrete large amounts of IgM, IgG, and IgA in 7-day cell cultures. The immunoglobulins (Ig) produced by cells responding to S. paratyphi B are not specific antibodies against the bacterial antigens. In comparison with other B cell activators (pokeweed mitogen, Staphylococcus aureus Cowan I, and lipopolysaccharide), S. paratyphi B stimulation produced greater amounts of IgM but less IgG than pokeweed mitogen (PWM) or S. aureus Cowan I; lipopolysaccharide failed to stimulate significant Ig production on day 7 in most cases. In addition, the response to S. paratyphi apparently did not require T cell collaboration. These results suggest that the B cell subpopulation(s) responding to S. paratyphi B may be more differentiated B cells than those responding to either PWM or S. aureus Cowan I. Peripheral blood mononuclear cells from five patients with common variable immunodeficiency without evidence of abnormal suppressor T cells or monocytes failed to respond to S. paratyphi B, whereas cells from two of the same patients responded well to S. aureus Cowan I and partially to PWM. Thus, S. paratyphi B appears to be superior to other B cell activators for studies of B cell function in normal and abnormal states.

Serum samples from 70 Caucasian patients with multiple sclerosis were typed for nine Gm markers. Significant association was found with the Gm 1,17;21 phenotype, and the relative risk for individuals with this phenotype was calculated at 3.6. The data indicate that Caucasians positive for Gm 1,17;21 are almost four times more likely to develop multiple sclerosis than those without this phenotype.

Gm, A2m, and Km allotypic markers were examined in 40 Caucasian patients with squamous cell carcinomas of the head and neck. Serum IgA levels, the A2m(1) allotypic marker, and antibodies against IgA1, A2m(1), and A2m(2) were measured quantitatively. The frequency of Km(1) was found to be significantly increased in patients with head and neck cancer as compared to the control population.

A population of 291 healthy North American Black subjects of different ages was studied for immunoglobulin (Ig) allotypes and the prevalence of autoantibodies, to determine possible associations between Ig allotypes and age, autoantibodies and age, and Ig allotypes and autoantibodies. Indirect immunofluorescence was used to detect anti-gastric parietal cell, anti-smooth muscle, anti-thyroid microsomal, anti-nuclear, and anti-mitochondrial antibodies. The sera were typed for the Ig allotypes Gm(1, 2, 3, 5, 6, 13, 14, 17, and 21) and Km(1) with a hemagglutination-inhibition assay. A significant association between advanced age and an increased prevalence of anti-nuclear antibodies was observed in females. There was no significant association between Ig allotypes and the autoantibodies tested. The results suggest that Ig allotypes are not involved in the development of autoantibodies in healthy Blacks.

Dialyzable leukocyte extracts (DLE) have been used to treat a variety of antigen selective, and broad spectrum immunodeficiency diseases with sometimes encouraging results. We describe here the clinical and laboratory responses to DLE therapy of 2 patients with epidermodysplasia verruciformis (EV), a chronic cutaneous infection with a variety of human papilloma viruses. One patient with longstanding (30 yr) disease and no improvement to previous therapy showed gradual yet definite resolution of extensive verrucae planae, plaque, tinea-versicolor-like, and tumor lesions scattered over his entire integument. Cessation of DLE therapy for a short time resulted in recurrence of partially regressed lesions and also in the development of new tumors in this patient. The second patient, a grandson of the first patient, with minimal disease showed no progression of the disease during DLE prophylaxis. A third subject (brother of patient number 2) received no DLE and served as a control. All 3 subjects demonstrated severely depressed levels of suppressor T cells, a defect in cell-mediated immunity that has not been hitherto reported in patients with EV. Finally, evidence is presented for a possible X-linked recessive mode of inheritance for susceptibility to EV.

The role of monocytes, B cells, and adherent and nonadherent T cells in the response of purified protein derivative of tuberculin (PPD) as measured by [3H]thymidine uptake in vitro has been explored. The response to PPD was found to be highly dependent on monocytes, to approximately the same extent as previously found for the responses to concanavalin A (Con A) and phytohemagglutinin. The response to PPD was also found to be highly dependent on a population of adherent T cells different from the adherent T cell population involved in the response to Con A. In the case of PPD, the effect was additive, as opposed to the potentiating effect seen for Con A. Further, the adherent T cells involved in the response to PPD were much more sensitive to hypotonic shock than those in the response to Con A. B cells were also found to be important in the response to PPD, although only to a slight extent.

The in vitro effects of ISO on the immune responses of cancer patients were investigated. Forty seven patients with primary tumors (26 lung carcinoma, 14 breast adenocarcinoma, 7 melanoma) were studied. Concanavalin A (ConA)-induced lymphocyte proliferation, natural killer cell (NK) activity, and monocyte chemotaxis were measured. In 40 of the 47 patients (85%), ConA-induced lymphocyte proliferation was depressed; NK activity was depressed in 32 (68%), and monocyte chemotaxis was found to be depressed in 36 (77%). For in vitro studies, an optimum concentration of ISO (100 micrograms/ml per 10(6) cells) was used to treat peripheral blood mononuclear cells. In the presence of ISO, all three parameters were restored to normal or near normal levels in those that were depressed. Under these preincubation conditions in vitro treatment of mononuclear cells from the peripheral blood of normal individuals with ISO had no effect on their activities in the three assays. Similar effects on these three immune parameters were observed when 24 h supernatants obtained from patients' mononuclear cells pretreated with ISO were employed in these assays.

Human T-cell subsets, defined by active E rosette formation, were examined for their ability to produce leucocyte migration inhibitory factor (LIF) in response to mitogen or specific antigen. It was determined that T cells enriched for active rosette-forming (A+) cells produced LIF in response to concanavalin A, whereas T cells depleted of active rosette-forming (A-) cells did not. Similarly, A+ cells from a tuberculin-sensitive donor produced LIF in response to tuberculin purified protein derivative, whereas A- cells from the same donor failed to produce the mediator. Thus, T-cell production of LIF in humans appears to be restricted to those T cells capable of active rosette formation.

A method of two-dimensional electrophoresis has been devised to allow the study of the electrophoretic mobility of urinary lysozyme. Three different phenotypes have been defined in a study of thirteen purified lysozymes obtained from different patients with monocytic leukemia.

Binding of human circulating T cells to established normal and malignant B cell lines results in rosette formation. The percentage of B cells, circulating T cells, and thymocytes able to bind to the B-LCL Raji were 0%, 59 +/- 4% and 61 +/- 6%, respectively. The percentage of rosettes formed between Raji cells and circulating mononuclear cells from 92 normal individuals was 27.8 +/- 5.3%, and remained stable over several months. This phenomenon seems to involve relatively mature B cells, and a T cell marker which appears early in T cell ontogeny. In the peripheral blood, most of the B-LCL binding T cells exhibit a 'helper-inducer' phenotype, as determined with the monoclonal antibodies Leu 3a and OKT4. However, a significant percentage of T cells with so-called 'cytotoxic-suppressor' markers (Leu 2a and OKT8) also bind to B-LCL. The T cells involved in this morphological interactive reaction with B cells might conceivably be specifically involved in regulating B cell functions. Enumeration of this particular subset may be useful in conditions where abnormal T-B cell interactions are suspected.

Mitogenesis and polyclonal immunoglobulin production in peripheral blood lymphocyte cultures activated with Formalin-fixed or autoclaved protein A-containing Staphylococcus aureus were studied. Direct evidence for a dissociation between cell proliferation and polyclonal immunoglobulin production was found, in that S. aureus was not mitogenic after being autoclaved but retained the ability to stimulate B cells to produce immunoglobulin. Trypsin-treated S. aureus lost its binding site for immunoglobulin G, but its mitogenicity was not altered; thus, the protein A binding site for immunoglobulin G on the bacterial cell wall is not required for the stimulation of lymphocyte proliferation. Our data also show a dissociation between cell proliferation and polyclonal immunoglobulin production induced by protein A coupled to Sepharose CL-4B. These results suggest the presence of three distinct active sites on the protein A molecule: one that binds immunoglobulin G molecules, one that stimulates cell proliferation, and one that stimulates polyclonal immunoglobulin production.

Carcinoembryonic antigen (CEA) activity was measured by radioimmunoassay in blood from cystic fibrosis (CF) homozygotes, heterozygote carriers of CF, normal healthy controls, and other patient controls with carcinomas involving gastrointestinal organs. All samples were also screened by electrofocusing for cystic fibrosis protein (CFP), a metabolic marker previously shown to be associated with the CF gene. Significantly increased levels of CEA activity were found in all CFP-positive groups; however, with one exception all patient controls with marked increases in CEA activity were CFP-negative. Immunodiffusion of perchloric acid extracts of CEA-like material from heterozygote carrier blood indicated that the CEA-like material, which was elevated in homozygotes and heterozygotes for CF, showed only partial identity with two separate CEA preparations obtained from colon carcinomas and was not identical to either A, B, or O(H) blood group substances. This glycoprotein material did, however, react with three different anti-CEA antisera. Our finding of an abnormally increased glycoprotein in cystic fibrosis, taken together with previous reports demonstrating abnormalities in the carbohydrate portion of glycoproteins found in various exocrine secretions in CF, further suggests that the primary defect in this disease is manifested partly as a defect in glycoprotein metabolism. This defect may result from an abnormality in one or more of the glycosyltransferases, possibly caused by a more primary defect in polyamine metabolism.

1. Calcium and immunoreactive parathyroid hormone (iPTH) levels were measured in sera of 1334 normal subjects ranging from newborn to over 80 years of age. Albumin was measured in samples from the population of adults, which was 80% white, 15% black and 5% oriental. 2. Serum calcium and iPTH levels in children tended to be higher in the first three years of age; no sex differences were noted. Values for serum calcium and iPTH were higher in children than in adults. 3. Serum calcium, iPTH and albumin showed more variation in groups of white, black and oriental women than in similar groups of men. In white females the mean serum calcium remained fairly constant until age 60, whereas in black women it rose steadily from age 20-29 until age 50-59. Serum iPTH levels were lower in black women than in white women and usually were not measurable in oriental women. 4. In men (white, black and oriental) there was a steady decrease in mean serum calcium with age, and iPTH levels were not different from those observed in white women. 5. Although the number of samples from oriental women was small, the serum calcium was consistently lower and serum albumin was constantly higher than in white or black women, and iPTH levels usually were unmeasurable.

Since seminal components can mediate immunosuppression in vitro, it is possible that some antigen(s) may be common to both the reproductive and immunologic systems. In a group of 70 couples with unexplained infertility, 50 "autoimmune" males and 40 "isoimmune" females had lower than normal percentages of total T cells (mean values +/- standard error of the mean 63 +/- 2% and 60 +/- 2% for immune males and females, respectively, versus 77 +/- 2% and 78 +/- 5% for 50 normal males and females, respectively; P < 0.001). Sheep red blood cell (SRBC) rosetting of lymphocytes was significantly reduced when SRBC were preincubated with sperm extracts (61 +/- 4% versus 9 +/- 2%; P < 0.001) but not when SRBC were incubated with normal serum or when lymphocytes were preincubated with sperm extracts. Antisperm antibody titers in the patients' sera (48 +/- 13) were correlated with their antithymocyte antibody titers (18 +/- 3) (P < 0.01). Moreover, antithymocyte antiserum (titer 1024) cross-reacted with sperm extract (titer 128), and vice versa. This cross-reactivity was significantly reduced by absorption of the sera with sperm cells (P < 0.001), thymocytes (P < 0.001), or white blood cells (P < 0.005). Absorption of autoimmune sperm extracts and seminal plasmas with thymocytes or sperm cells reduced the Coombs' titers, especially immunglobulin G (P < 0.01) and immunoglobulin A (P < 0.025). Similar results were obtained in passive hemagglutiation, immunofluorescence, and cytotoxicity assays. We conclude that sperm and T cells share a common antigen(s).

The P2 protein of bovine nerve root myelin was radiolabeled with 125I in homogeneous solution by the chloramine-T method and purified by gel filtration on Sephadex G-75 to obtain monomeric 125I-P2. Antigen-antibody complexes were isolated by the silica gel, double antibody, or polyethylene glycol techniques by using rabbit antibody to P2. As little as 1 ng/ml P2 could be detected. The RIA was used to measure the P2 content in nerve tissue and isolated myelin. The presence of P2 in spinal cord as well as in the peripheral nervous system was confirmed. Peptides isolated by CNBr digestion of the P2 protein were tested in the RIA. CN-1, comprising 80 to 90 residues from the interior of the molecule displayed complete immunologic cross-reactivity with intact P2. Neither CN-2, representing 18 amino acids from the COOH terminal, nor CN-3, representing 20 amino acids from the NH2 terminal, showed cross-reactivity. Since the major determinant for experimental allergic neuritis in the rabbit is located in peptide CN-2, our present data suggest that the major neuritogen and the major determinant(s) for humoral antibody response in this species may be at different locations within the P2 molecule.