Transfer Factor Therapy Research Articles

Report of a patient with T-cell deficiency and normal B-cell function: A new immunodeficiency disease with response to transfer factor

An 11-yr-old boy had recurrent fevers and pulmonary infections since early childhood and, at age 7, had disseminated varicella with bilateral pneumonitis. A female sibling, age 1, died during this period of time with varicella pneumonia. Two years later, an immunological evaluation showed severe deficits in cellular immunity with skin anergy and very low or poor in vitro lymphocyte proliferative responses to mitogens, allogeneic cells and specific antigens. Quantitation of peripheral T-cells by spontaneous rosette formation was also low—40–45% (normal 61%). On the other hand, B-cell immunity seemed to be completely normal. Serum immunoglobulins and the immunoglobulin receptors on peripheral lymphocytes were normal. The patient produced specific antibodies upon antigen challenge (immunization) and after natural infection. Following transfer factor therapy, conversion of skin reactivity and clinical improvement occurred. No changes were seen in in vitro lymphocyte function with transfer factor therapy. Immunologic reconstitution persisted for 6 mo, after which the patient responded again to the administration of transfer factor. Although this patient has several characteristics in common with Nezelof's syndrome, the patient described in this report appears to represent a distinct clinical entity of primary isolated T-cell deficiency and normal B-cell immunity. The normal B-cell immune system, and the clinical and immunological response to transfer factor therapy, differentiates our patient from the syndrome of thymic dysplasia with immunoglobulin synthesis (Nezelof's syndrome).

Therapy of cytomegalovirus retinitis with transfer factor

A renal transplant recipient who was rapidly losing his vision due to cytomegalovirus (CMV) retinitis was treated with transfer factor (TF). TF was prepared from lymphocytes of a subject with CMV mononucleosis who had cell-mediated immunity to CMV as assayed by lymphocyte transformation ([ 3H] thymidine uptake) and migration inhibitory factor (MIF) production. Within 2 mo of initiation of TF therapy, all of the patient's foci of retinal inflammation became inactive. This was his second episode of acute retinitis within 4 yr. The first one required reduction in the dose of immunosuppressants to achieve remission, whereas during the present exacerbation, immunosuppressants were maintained at a pre-TF therapy dosage. It is of interest that immediately after initiation of TF, a previously quiescent area of retinitis became inflamed; however, after several additional doses of TF, this reactivation subsided. In addition, the patient developed (though transiently) a positive delayed skin test to one of the antigens (SK-SD) to which the donor of the TF was sensitive, and although lymphocyte transformation by CMV antigen remained negative, there was evidence of MIF production. Finally, the patient's urine CMV titer declined from persistently high titers of 10 3.5 to 10 4.5 TCID 50 to a titer of 10 0.5 TCID 50, which was the lowest observed during the 4 yr of study. We conclude that it is unlikely that these findings were due to chance. TF should receive wider clinical trials in certain viral infections, particularly in immunosuppressed hosts.

The use of transfer factor in a patient with agammaglobulinemia.

We have studied a 9-year-old boy with agammaglobulinemia treated for the past 6 years with exogenous gamma-globulin who was noted to have an immunoglobulin (Ig)M level of 35 mg/100 ml and circulating B cells as determined by immunofluorescence. Of the circulating lymphocytes, 41% had alpha-immunoglobulin heavy chains, 3% gamma chains, and 3% mu chains. Synthesis of gamma heavy chain classes showing wide heterogeneity and alpha and mu chains of restricted mobility was demonstrated by radioimmunoelectrophoresis. Because of the patient's poor clinical response to exogenous gamma-globulin administration and the paradoxic presence of circulating B cells, with the capacity to synthesize immunoglobulins in vitro, we elected to begin a course of therapy with transfer factor. After the initial four doses of transfer factor (2 x 10(8) lymphocytes/dose) his serum IgG rose from 50 to 130 mg/100 ml, the same level which he had previously attained during continuous exogenous gamma-globulin therapy. His serum IgG has remained at this level for the past 12 months with trimonthly booster doses of transfer factor. The patient has not required any additional gamma-globulin therapy and he has remained clinically asymptomatic. Our studies in a patient with agammaglobulinemia have shown that transfer factor therapy may affect immunoglobulin synthesis. The concurrent discontinuation of exogenous gamma-globulin administration makes it difficult to attribute the changes to only one or another aspect of therapy. We await further reports of the effects of transfer factor in the therapy of patients with B cell disorders.

Immunologic Reconstitution in Man—Present Status

Recent advances in immunobiology have shed new light on our understanding of the essential role of immunity as it relates to body economy. Immunity, once thought to be the primary defense mechanism against microbial infection, appears to have a much broader function--recognition and elimination of foreign bodies and preservation of the integrity of the individual. As our understanding of the pathophysiology of the immune system became more clear, immunologic reconstitution emerged as a new, promising mode of treatment for a variety of diseases with immunodeficiency. Bone marrow transplantation, thymus transplanation, transfer factor therapy, infusion of leukocytes, BCG vaccination, and other specific or nonspecific immunostimulants have been tried, with dramatic beneficial results in some instances. Although still in its infant stage, this form of treatment appears to have great potential and wide application in the prevention and treatment, not only of primary immunodeficiency, but also of many other diseases such as cancer, the so-called autoimmune diseases, and even aging.

Therapeutic use of transfer factor.

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.

The hemolytic-uremic syndrome in siblings: A prospective survey

sixth leucocyte culture conference, New York, 1972, Academic Press, Inc. 3. Rosenber SA, and David, JR: Inhibition of leukocyte migration: An evaluation of this in vitro assay of delayed hypersensitivity in man to a soluble antigen, J Immunol 105:1447, 1970. 4. Wybran J, Carr MC, and Fudenberg HH: The human rosette-forming cell as a marker of a popul~ttion of thymus-derived cells, J Clin Invest 51:2537, 1972. 5. Lawrence HS: Specific recruitment ofimmunocompetent cells by transfer factor, in Lawrence HS, and Bandy M, Editors: Mediators of cellular immunity, New York, 1969, Academic Press, Inc., p. 143. 6. Cooper MD, Chase HP, Lowman JT, Krivit W, and Good RA: Wiskott-Aldricb syndrome, an immunologic deftciency disease involving the afferent limb of immunity, Am J Med 44:499, 1968. 7. Oppenheim J J, Blaese RM, and Waldmann TA: Defective lymphocyte transformation and delayed hypersensitivity in Wiskott-Aldrich syndrome, J Immunol, 104: 835, 1970. 8. Spitler LE, Levin AS, Stites DP, Fudenberg HH, Pirofsky B, August C S, Stiehm ER, Hitzig WH, and Gatti R: The Wiskott-Aldrich syndrome, results of transfer factor therapy, J Clin Invest 51:3216, 1972. 9. Baldini, MG: Nature of the platelet defect in the WiskottAldrich syndrome, Ann N Y Acad Sci 201:437, 1972. 10. Krivit W, and Good RA: Aldrich's syndrome (thrombocytopenia, eczema and infection in infants), Am J Dis Child 97:137, 1959.

RECONSTITUTION OF CELLULAR IMMUNITY IN PATIENTS WITH SEVERE COMBINED IMMUNODEFICIENCY BY FETAL THYMUS TRANSPLANTATION AND TRANSFER FACTOR

Reconstitution of cellular immunity in 3 infants occurred following intraperitoneal fetal thymus transplantation and Transfer Factor therapy. In all 3, the earliest evidence of reconstitution was a rash consistent with graft vs host reaction (GVHR) with onset 10 to 14 days following transplant. Mild GVHR occurred in the 1- and 4-mo old infants who were apparently free of infection at the time of thymus transplantation from 12- and 14-week fetuses. These 2 infants are alive and well at age 2-½ yr and 11 mos. Severe GVHR occurred in the S-mo old infant following thymus transplant from a 16-week fetus; the infant was receiving therapy for pneumocystis carinii at the time of transplant. The child died 10 wks post-transplant with GVHR and pulmonary disease. The sequence of cellular reconstitution in all infants was lymphocyte response to allogenic cells, phytohemagglutinin, and T-cell rosette formation and occurred 3 to 12 wks following transplantation. Cell chimerism was detected by HL-A typing in 2 infants. Reconstitution of antibody-mediated immunity was not observed. Successful reconstitution in these patients, in contrast to earlier experience, was probably related to 3 factors: synergism between thymus and Transfer Factor, transplant of thymus within 1 hr after fetal abortion, and transplantation prior to severe infection.

Transfer factor: Therapy in patients with deficient cell-mediated immunity and deficient antibody-mediated immunity

The effect of transfer factor therapy on the clinical and laboratory abnormalities of six patients with various antibody and cell-mediated immunodeficiency disorders was evaluated. Clinical improvement occurred in three patients. Conversion of previously negative delayed hypersensitivity reactions occurred in the same three patients. One patient demonstrated an increased in vitro lymphocyte response to phytohemagglutinin. No change in antibody mediated immunity was observed in any patient.

PARTIAL RECONSTITUTION OF A PATIENT WITH CONGENITAL THYMIC DYSPLASIA BY FETAL TISSUE AND TRANSFER FACTOR

Attempts at immunologic reconstitution of patients with congenital thymic dysplasia have been disappointing. We have studied an 18 month old male with chronic history of mucocutaneous candidiasis (CMC), diarrhea, repeated infections and failure to thrive. He had a marked deficiency of T-cell functions with a decrease in circulating T-cells, absent cutaneous reactivity to skin test antigens and absent PHA responsiveness in vivo and in vitro. Although lymphopenic he had adequate numbers of circulating B-cells and plasma cells in his bone marrow aspirates. B-cell functions including levels of serum immunoglobulins, isohemagglutinins and pokeweed mitogen responsiveness were within the normal range. Implanted tissues from a female abortus of 16 weeks gestation restored in vivo and in vitro PHA responsiveness within 24 hours. Karyotypic and HL-A analyses demonstrated that chimerism had not occurred. In an attempt to augment persistently negative responses to Candida antigen, multiple doses of transfer factor (2.4 × 108 lymphocytes/dose) were administered. Peripheral T-cell rosettes increased from 5% to 40% without change in his response to Candida antigen or his clinical CMC. After eight months of continuing transfer factor therapy the patient has tripled his weight and remains clinically stable.

Transfer factor therapy in a case of complex immunodeficiency

A young woman with unclassified complex immune deficiency disease characterized by relapsing skin ulcerations, greatly depressed cellular immunity, absent serum IgA, and inability to develop circulating antibodies to typhoid vaccine, was treated twice with the dialyzable transfer factor from normal persons. Following such therapy she showed clinical improvement and strong delayed skin sensitivity to Candida, streptokinase-streptodornase, and moderate, rather short-lived hypersensitivity to PPD. In addition, she could be sensitized to dinitrochlorobenzene and her leucocytes responded normally to phytohaemagglutinin; all these manifestions of cellular immunity had been absent prior to therapy. She acquired the capacity to develop anti-typhoid antibodies. These findings appear to indicate that dialyzable transfer factor not only transfers delayed-type hypersensitivities preexisting in the donor but is also able to remedy hitherto unspecific defects existing in certain forms of immune deficiency.

Effect of transfer factor therapy on mixed lymphocyte culture reactivity.

We have studied the effect of dialyzable transfer factor therapy on three patients with immunodeficiency disease and in one patient who demonstrated no evidence of deficiency of either humoral or cellular immunity. We found evidence for nonspecificity in the effect of transfer factor on mixed lymphocyte culture reactivity. The data suggest that in patients with immunodeficiency disease a maturation of lymphocytes may lead to a generalized increased immune responsiveness. More profoundly, our data show that transfer factor may induce changes in the expression of histocompatibility determinants. We observed changes in the expression of determinants capable of stimulating in the mixed lymphocyte culture reaction as well as an increase in the capacity of lymphocytes to respond.

Treatment of infectious and neoplastic diseases with transfer factor.

The efficacy of restoration of cellular immunity in therapy of patients with certain chronic in-infectious or neoplastic diseases is under evaluation in several centers. Theoretically, a substance such as transfer factor is an ideal candidate for this therapy. Transfer factor, a dialyzable substance from blood leukocytes, selectively endows recipients with the cellular immune responses of the leukocyte donors, but does not induce antibody synthesis. Moreover, it does not contain intact leukocytes and therefore does not sensitize the recipient to HL-A antigens and cannot induce graft versus hostdisease. This review summarizes the current status of transfer factor therapy and points out the need for controlled clinical trials.

Editorial: Transfer-factor therapy of immunodeficiencies.

Approximately 20 years ago H. Sherwood Lawrence described the specific transfer of delayed hypersensitivity with use of a dialysable fraction obtained from extracts of human lymphocytes. The materi...

Transfer factor therapy in a patient with progressive primary tuberculosis.

Transfer factor was administered to a patient with progressive primary tuberculosis who failed to respond to antituberculous therapy and in whom a defect in cellular immunity to tuberculous infection was shown by in-vivo and in-vitro studies of cell-mediated immunity. The administration of transfer factor to this patient resulted in the development of immunologic reactivity, which was accompanied by dramatic improvement of her clinical condition. This observation strongly suggests that transfer factor in conjunction with antituberculous therapy was instrumental in the resolution of the patient's infection.

The effect of transfer factor therapy on tumor immunity in alveolar soft part sarcoma

A young man with alveolar soft part sarcoma and his identical twin were studied in terms of immunologic response to the patient's tumor homogenate. The lymphocytes from both twins underwent lymphoblastic transformation to tumor homogenate but only the healthy twin's lymphocytes released demonstrable migration inhibition factor (MIF) to the tumor preparation. Transfer factor was prepared from the healthy twin and administered to the tumor-bearing twin. A total dose of transfer factor equivalent to 45 × 10 8 lymphocytes given in three separate doses produced a persistently positive MIF assay in the patient. The tumor neither regressed nor progressed during the 6-month period after transfer factor therapy.

Transfer factor therapy in immune deficiency states.

Transfer factor therapy in immune deficiency states.

The Wiskott-Aldrich syndrome. Results of transfer factor therapy.

12 patients with Wiskott-Aldrich syndrome were treated with therapeutic doses of transfer factor in an attempt to induce cellular immunity. Clinical improvement was noted after transfer factor therapy in 7 of the 12 patients treated. Because this disease has a variable course and temporary spontaneous improvement can occur, the observed improvement cannot necessarily be attributed to the transfer factor. However, in two patients repeated remissions consistently followed transfer factor administration on repeated occasions. This included freedom from infections, regression of splenomegaly, and clearing of eczema. An unexpected finding was a decrease in bleeding in 3 of the 10 patients who had bleeding. Conversion of skin reactivity was obtained in all seven patients who clinically seemed to respond to transfer factor. In vitro studies performed after the administration of transfer factor demonstrated that the lymphocytes of the patients now produced migration inhibitory factor in response to appropriate test antigens, but did not undergo increased radioactive thymidine incorporation in response to the same antigens. A defect in the monocyte IgG receptors has been found in certain patients with the disease, and the current study shows that all patients with defective monocyte IgG receptors responded to transfer factor, whereas only one patient with normal receptors showed any response. This test may thus prove to be useful in predicting the results of transfer factor therapy in patients with Wiskott-Aldrich syndrome, although evaluation of a larger series of patients will be necessary to confirm this point. We conclude that cellular immunity can be induced, that there appears to be clinical benefit in certain patients with Wiskott-Aldrich syndrome by the use of transfer factor, and that this mode of therapy warrents trial in these patients and others with defects of cellular immunity.