Nathan Trainin

Immunological enhancement of tumor growth by syngeneic thymus-derived lymphocytes.

The role of lymphoid cells in the development of a transplanted syngeneic Lewis lung tumor (3LL) was investigated. It was found that thymocytes or thymus-derived lymphocytes could stimulate 3LL tumor growth in the recipients. This enhancing effect was manifested by a higher number of tumor takes, acceleration of tumor growth, and an increase in metastatic incidence. Lymphocytes from tumor-bearing mice were more effective than lymphocytes from nontumor-bearing controls in the manifestation of this phenomenon. Mice partially deprived of their T cell population by adult thymectomy manifested a striking reduction in tumor development.

Thymic hormones: inducers and

The first evidence of the thymuss pivotal role in immune, function was gathered by experiment and clinical observation more than 20 years ago. Nathan Trainin and his colleagues have helped to establish the link between the endocrine mechanism of the thymus gland and its immunological function. Here they describe the chemistry, biochemistry, and biological effects o f hormones isolated from or originating in the thymus(1-3).

Skin initiating action and lung carcinogenesis by derivatives of urethane (ethyl carbamate) and related compounds

Abstract The possibility that a metabolite might be implicated in the carcinogenic action of urethane on the lungs, and in its limited “initiating” action in the case of skin carcinogenesis, prompted the testing of a number of derivatives and analogues of urethane for both lung carcinogenesis and skin initiation in mice. The modifications in molecular structure of urethane involved (i) changes in the carbamyl portion, (ii) changes in its carboethoxy portion, (iii) phosphorylated derivatives, and (iv) addition compounds with keto and amino acids. Most of the compounds tested proved inactive, and among those that did give positive results, the effects were weak ; thus indicating that none of them represented the sought-for metabolite. Some tentative implications of the results are discussed as pointers for further enquiry.

Increased mitogenic reactivity of normal spleen cells to T lectins induced by thymus humoral factor (THF)

Abstract When normal spleen cells were incubated for 24 hr in medium containing thymic humoral factor (THF) and then stimulated by phytohemagglutinin (PHA) or concanavalin A (Con A), a significant increase in the mitogenic reactivity of these cells was observed. When stimulation to T lectins was performed simultaneously with THF, a strong inhibition in cell reactivity was found. It seems that these opposite effects of THF on cell reactivity to T lectins are determined by the sequence of events which lead to maturation of lymphoid cells. Thymic humoral factor does not modify the response of cells to B mitogen lipopolysaccharide (LPS), thus suggesting that this maturative effect on lymphoid cells is exerted on T lymphocytes only.

Increase in antibody-forming cells of neonatally thymectomized mice receiving calf thymus extract.

DEVELOPMENT of the mammalian lymphoid system and attainment of full immunocompetence have been shown to depend on the presence of the thymus during early life1–3. The possibility has been considered that the multiple functions of the neonatal thymus are effected not only by migration of viable thymocytes or cells preformed elsewhere which become competent within the environment of the thymus, but also by means of a diffusible substance secreted by the thymus and affecting differentiation of lymphocytic cells outside this organ. Evidence for such a humoral mechanism has accumulated from studies of the ability of thymic tissue contained within cell-tight diffusion chambers to prevent the deficiencies resulting from surgical removal of the thymus. Specifically, mice implanted intraperitoneally with chambers allowing passage of fluids but not of intact cells showed neither depletion of lymphocytes of peripheral blood and lymphoid organs nor characteristics of the wasting syndrome which follows thymectomy of newborn animals4. Furthermore, the ability to form antibodies in a primary response against sheep erythrocytes was, to a large extent, maintained5, as was the capacity of neonatally thymectomized mice to reject skin homografts6. The non-cellular nature of this thymic substance has been confirmed by studies of the restorative effects of a cell-free component extracted from thymus of xenogeneic species. In neonatally thymectomized mice, wasting disease was prevented and the normal lymphocyte population of peripheral blood and spleen was maintained by injection of such extracts7,8. Furthermore, the abilities of such mice to reject both skin grafts and tumours were partially restored and graft versus host reactivity was partly returned to the spleen cells of thymectomized mice by calf thymus extracts9,10.

Thymus cell population exerting a regulatory function in the immune response of mice to polyvinyl pyrrolidone

Abstract An increased response to PVP was observed after adult thymectomy and was partially reversed either by thymus implantation or by a single injection of thymic cells. In addition, an injection of thymic cells was found to reduce the response to PVP in normal recipients. An enhanced response to PVP was measured in B mice compared to that of normals. In such mice reduction of the response to PVP was observed when repeated doses of thymus cells were administered. Lower doses of HC resistant thymus cells strongly inhibited the response to PVP. The cells involved in the thymus regulatory function appear to be radiosensitive, since it was shown that radiation by itself resulted in an increased response to PVP. This inhibitory function of the thymus seems to disappear relatively early in progression of life, as seen by an increased response to PVP in elder mice. These results indicate that a T cell population exerts a regulatory function in the immunological response to PVP that was previously considered to be thymus independent.

SEVERE DISSEMINATED ADENOVIRUS INFECTION SUCCESSFULLY TREATED WITH A THYMIC HUMORAL FACTOR, THF

Abstract. Adenovirus and other usually benign viral infections may occasionally be associated with severe fulminant disease, often accompanied by acute acquired cellular immunodeficiency. Thymic humoral factor derived from calf thymuses has been demonstrated to have the capacity to restore the immunocompetence of immature, incompetent T cells. This factor was used in the treatment of a 3½‐year‐old boy who was critically ill with an adenovirus infection and presented evidence of immunocellular deficiency. Within less than 48 hours after the institution of treatment with thymic humoral factor there was a dramatic, progressive clinical improvement, with restoration of the cellular immunocompetence. It is suggested that thymic humoral factor may be beneficial in the treatment of severe viral infections associated with depressed cellular immunocompetence.

Some characteristics of a thymic humoral factor determined by assay in vivo of DNA synthesis in lymph nodes of thymectomized mice

Abstract An improved method for determining the activity of the thymic humoral factor (THF), by means of its enhancement of 3 H-thymidine incorporation into lymph node DNA, is described, using thymectomized mice for greater sensitivity. The active component of THF was found to be a heat-labile macromolecule, susceptible to pronase digestion. Fractionation of calf thymus extract by ammonium sulphate resulted in a partial separation and concentration of THF activity from several other inactive proteins in the extract.

Control of autoreactivity by a humoral factor of the thymus (THF)

Abstract Anti-self reactivity of autosensitized lymphocytes was evaluated by assay of the capacity of these cells to induce an in vitro GVH response against syngeneic tissue, and confirmed by induction of a syngeneic GVH response in vivo and by measurement of the proliferation of the sensitized cells in a syngeneic MLC. The anti-self reactivity manifested by spleen or thymus cells after sensitization on monolayers of syngeneic fibroblasts was clearly inhibited by addition of the thymic humoral factor (THF) to the lymphocytes undergoing or about to undergo sensitization. When these lymphocytes were obtained from neonatally thymectomized mice, inhibition of self reactivity by THF occurred simultaneously to THF-mediated acquisition of allogeneic reactivity in the same cell suspension. Spleen cells from neonatally thymectomized mice also exhibited directly the capacity to induce a syngeneic GVH reaction, indicating that in the absence of the thymus these cells had undergone autosensitization in vivo . This autoreactivity was prevented by incubating the in vivo -sensitized cells with THF. Also the in vivo GVH response elicited by spleen cells from neonatally thymectomized mice in syngeneic animals was inhibited by injection of THF to the donor mice. It is postulated here that thymic involvement in the processes controlling autoreactivity is at least partially mediated by THF.

T Lymphocyte Subsets and Function in the Peripheral Blood of Patients with Urological Cancer

The phenotypic distribution and immune reactivity of T lymphocyte subpopulations from peripheral blood of 50 patients with urological cancer were determined. Included were 36 patients with bladder transitional cell carcinoma, 7 patients with renal cell carcinoma and 7 patients with prostatic carcinoma. Thirty-eight age-matched patients with benign urological disease served as controls. A depression in immune competence was found in the group of male patients with infiltrating bladder cancer. In more than 50% of the patients with infiltrating bladder carcinoma, the T helper (CD4) subset was reduced with a concomitant inversion in the CD4/CD8 ratio and impairment in the T cell function as determined by the ability to proliferate upon phytohemagglutinin and concanavalin stimulation. Patients with superficial bladder carcinoma, as well as those with renal cell carcinoma had an immune profile similar to that of the control group. The group of patients with prostatic carcinoma had higher mean CD4/CD8 ratios than the control group, resulting from decreased suppressor/cytotoxic cells. Our results have indicated that the characterization of T cell subset and lymphocyte activity correlated well with the histopathologic state of patients with bladder carcinoma. Thus, the determination of the CD4/CD8 ratio may prove a valuable method for monitoring patients with bladder carcinoma, in addition to serial urine cytology, random urothelial biopsies and flow cytometry.