CURRENT DEVELOPMENTS

Transfer factor and possible applications in gynecology RALPH

S. FREEDMAN,

J. TAYLOR FELIX JOSEPH Houston,

M.D.,

WHARTON,

RUTLEDGE, G.

PH.D.*

M.D. M.D.

SINKOVICS,

M.D.

Texas

Dialyzable transfer factor (TM) is reviewed against its historical background, preparation methods, physiochemical properties, possible mechanisms of action, pharmacology, and clinical studies, including several areas relating to gynecology. The possible role of TM as an adjunct in the treatment of cancer is discussed. The discussion centers’on gynecologic cancer in several patients who have received TM. The difficulties and future possibilities for this modality of treatment are considered. (AM. J. OBSTET. GYNECOL. 130: 572,1978.)

immunotherapy are well established in gynecology in rhesus disease and infertility. The development of these modalities in gynecology have opened new vistas for the gynecologist, with subsequent study, exploration, and expansion into these fields. Immunology offers promise for the development of new methods in the diagnosis and treatment of malignancy. Transfer factor is currently being investigated along with C. parvum as an adjunct to the treatment of some gynecologic malignancies at the M. D. Anderson Hospital and Tumor Institute. A review in this area with consideration of some applications in gynecology is, therefore, both pertinent and timely. IMMUNODIACNOSIS

AND

From the Department of Gynecology and the Section of Clinical Tumor Virolo& a&d Imn&nology, Department of Medicine. The Universitv of Texas Svstem Cancer Center, M. D. Aki~rson Hospitk and Tumdr Institute. Reprint requests: Dr. Ralph S. Freedman, Department Gynecology, M. D. Ana’enon Hospital and Tumor Institute, 67.23 Bertner Ave., Howton, Texas 77030. *Sponsored Committee.

572

by Eli Lilly

W Co. Intentational

Fellowship

of

Historical background Bloom and Chase’ have critically reviewed the evidence for the transfer of delayed hypersensitivity (DHS) response in man and animals. It appears that the transfer of DHS to old tuberculin was first performed in 1909, in guinea pigs, with defibrinated blood used as the vehicle for the transferred immunity. It was not until 1942 that Landsteiner and Chase’ succeeded in performing this experiment with living lymphoid cells. DHS was originally observed by Zinsser3 as a manifestation of cell-mediated immunity (CMI) and to be distinct from the immediate or antibody-mediated response, also known as humoral immunity. CM1 has been implicated as a defense mechanism against some bacterial, viral, and fungal infections, and more recently an analogy has been drawn with mechanisms purported to be responsible for early recognition and elimination of malignant cell clones.* Many of the studies with transfer factor have utilized DHS skin testing and the necessity of examining its relationship to host immune response and, in particular, CM1 is, therefore, apparent. As with allograft re000%9378/78/05130-0572$01.30/O

@I 1978 The C. V. Mosby Co.

Volume

130

Number

5

jection, the DHS skin response to primary or recalled skin antigens produces a local infiltration of mononuclear cells that consists of both lymphocytes and monocytes. Delayed hypersensitivity is but one manifestation of CMI. which can also be evaluated in vitro by enumerating and studying the functions of the T lymphocytes. Patients who have a primary immunedeficiency state such as thymic gland hypoplasia are incapable of a cell-mediated response.5 Direct contact is required between the antigen or allergen and the responding cells for CM1 to occur. This is of considerable importance when the transfer of DHS is considered. Following sensitization, the same agent is required to elicit a recall response but normal animals can sometimes be rendered tolerant or insensitive to sensitization, as the result of suppressor lymphocyte activation. Paradoxically. immune suppression with cyclophosphamide can restore or enhance responsiveness resulting from the extreme sensitivity of the suppressor T cell population to this drug.6 In the experiment of Landsteiner and Chase, DHS was transferred with living lymphoid cells from donor guinea pigs, made immune to picrylated red cell stromas. to nonimmune recipients. Chase7 obtained a similar response to tuberculin in 1945, and in 1949, Lawrence8 transferred cellular immunity to tuberculin in man with non-glass-adherent living lymphoid cells.’ The duration of the transferred immunity was brief, lasting several days in the guinea pig but several months in man, depending upon which antigen was used to demonstrate the transferred immunity.8-‘a Since these earlier experiments, the transfer of immunity to bacterial antigens and plant allergens has frequently been observed but the transfer of contact sensitivity to primary sensitizing chemical agents such as dinitrochlorobenzene (DNCB) and dinitrofluorobenzene (DNFB) has been difficult to substantiate in man.‘, ” It has also been difficult to differentiate direct toxicity of the chemical agent from immunologic effects, particularly when larger concentrations of the chemical were used.’ Prior testing with chemical reagents and the use of chemical depilation before antigen application further confused the interpretation of these tests by possibly causing active sensitization. In addition, pre-existing immunity to both DNCB and DNFB has been found in 1 to 2 per cent of patients. These substances may be present in some dyes used by pottery makers or photographers and in some refrigerant solutions.” When living lymphoid cells are used to transfer immunity, reactivity to the antigens may be seen as early as four hours but usually not later than 48 hours after

Transfer

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sensitization. The response may persist frlr many years in some patients. In 1955, LawrenceI showed that an extract of. lymphoid cells from sensitive donors was as effective as viable cells in transferring immunity to tuberculin and streptococcus M substance. The response was cellmediated and unrelated to antibody formation and was of long duration. The number of cells used to produce the lysate and the duration and intensity of the donors’ past immune experience influenced the ‘ype of response observed. This experiment further revealed that DHS to tuberculin could be serially transferred between individuals with leukocyte exrracts derived from a sensitized individual as early as the third day and as late as the third week following rile initial transfer of immunity. This has recently been confirmed by DHS skin testing, macrophage-inhibitor! factor release, ‘and lymphocyte transformation assays.‘” These studies indicate that antigen transierral through the leukocyte extract preparations is unlikeh. The term “transfer factor” was introduced in 1956, to indicate the active principle(s) in the leukocyte extract responsible for the transfer of sensitivity.” The transfer of sensitivity to bacterial and chemical antigens provided the main supporting evidence for the transfer of DHS. In 1960, Rapaport and ‘tssociates” extended the field to include fungal diseases by transferring coccidioidin sensitivity to natives of New York with leukocyte extracts from Californian subjects. Thirteen of 16 recipients who had negative responses to coccidioidin had positive responses after receiving extracts from sensitive donors. This study has fl equently been quoted as providing substantial evidence for the transfer of specific immunity, but five of eight recipients had positive responses after receiving extracts from donors who were not sensitive to coccidioidin. Conclusions derived from this study have been furt.her c.riticized since active sensitization of the recipients c&d have occurred when they were pretested. In 1960, Lawrence and associates15 showed that repeated immunization of individual A with skin derived from individual B resulted in a cell extract prepared from the lymphocytes of individual A that was capable of accelerating the rejection time of a graft donated by individual B to individual C. ‘l‘he rejection time was more rapid than that observed when skin was grafted directly from subject A to subject

Transfer factor and possible applications in gynecology.

CURRENT DEVELOPMENTS Transfer factor and possible applications in gynecology RALPH S. FREEDMAN, J. TAYLOR FELIX JOSEPH Houston, M.D., WHARTON, R...
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