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Association of anergy with an immunosuppressive peptide fraction in the serum of patients with cancer.

Abstract To study the relation between circulating immunosuppressive factors and anergy in patients with cancer, we tested 53 patients with cancer for hypersensitivity to skin-test antigens and 2,4-dinitrochlorobenzene. Of 41 patients with negative skin tests, 27 (66 per cent) had immunosuppressive serum (≥70 per cent inhibition of lymphocyte stimulation by phytohemagglutinin). None of 12 with positive skin tests had immunosuppressive serum. Thus, anergy and serum immunosuppressive activity were correlated (p<0.05). After ion-exchange chromatography, most of the immunosuppressive activity in cancer serum was in the first peak, fraction I. The same fraction from subjects without cancer contained no detectable immunosuppressive activity. Mean total immunosuppressive activity of cancer serum was 166.0 ± 97.5 (S.D.) units, and that of non-cancer serum was 30.4 ± 9.2 units (p<0.05). Diafiltration of fraction I. from cancer serum yielded a fraction (< 10,000 daltons) that was highly immunosuppressive. Thus, ane...

Clinical Use of Rabbit Antihuman Lymphocyte Globulin in Cadaver-Kidney Transplantation

Abstract Twenty-six consecutive recipients of cadaver-kidney transplants were treated with rabbit antihuman lymphocyte globulin (ALG) in addition to conventional immunosuppressive therapy. Each of the first 10 of these recipients has been followed for more than 12 months. The one-year transplant survival in this group was 90 per cent. Rabbit ALG administration was well tolerated. Most patients had no symptoms related to ALG injections. There were four acute transplant rejection episodes in the first 10 patients and four episodes in 16 subsequent patients followed for more than four months. All acute rejection episodes occurred six weeks or more after transplantation, and all were easily and promptly reversed by a temporary increase in the dose of steroid therapy. Immediate, hyperacute rejection by preformed antibodies was the only cause of kidney transplant loss in the entire series.

Phytohemagglutinin stimulation of human lymphocytes. Failure to detect an early increase in cyclic AMP concentration.

Abstract Cyclic AMP content and adenylate cyclase activity were determined in human lymphocytes stimulated to proliferate by phytohemagglutinin (PHA). Both commercial (Difco PHA-M) and purified PHA were used at optimal stimulatory concentrations as confirmed by incorporation of [14C]leucine. Cyclic AMP levels were measured by radioimmunoassay. Exposure of lymphocytes to PHA-M alone yielded no significant change in intracellular cAMP levels; however, in the presence of the phosphodiesterase inhibitor, caffeine, PHA-treated cells had lower levels of cAMP than the caffeine controls. That adenylate cyclase remained active in these experiments was shown by marked increases in lymphocyte cAMP levels following exposure to prostaglandin E1 (PGE1). Stimulatory concentrations of PHA-M or purified PHA also failed to induce adenylate cyclase activity in lymphocyte particulate preparations whereas PGE1 or NaF produced significant increases in enzyme activity. Moreover, PGE1, at concentrations which caused a prompt and significant rise in adenylate cyclase activity and in intracellular cAMP levels, inhibited lymphocyte stimulation by PHA.

Inhibition of secondary immune responses in vivo by immunoregulatory alpha globulin (ira).

Summary These studies demonstrate that IRA will suppress both primary and secondary immune responses as measured by a hemolytic plaque assay. Suppression of the secondary response occurs whether IRA is administered prior to the immunizing injection of antigen or prior to the challenge injection of antigen. The fact that IRA administered at the time of initial antigen exposure was able to inhibit the response to a second, or challenge, dose of that antigen; and that the secondary response was significantly less than a normal primary response suggests that IRA administered at the time of initial antigen exposure confers partial tolerance to that antigen.

The prolongation of renal allograft survival by an immunosuppressive peptide isolated from human plasma.

Immunoregulatory α-globulin (IRA), a naturally occurring immunosuppressive peptide isolated from pooled normal human plasma, was administered to Lewis rats before allografting of LBNF1 kidneys. Control Lewis rats received either no treatment or inactive human peptide before kidney allografting. Median survival was 10.0 ± 2.2 (SD) days and 9.0 ± 1.0 days in Lewis rats receiving inactive peptide or no treatment, and 21.0 ± 1.9 days in Lewis recipients treated with IRA, P < 0.05. Three IRA-treated recipients were long-term survivors. At a time when the direct immunosuppressive effect of IRA was long absent, the serum of the long-term survivors could block the killing of LBNF1 target kidney cells by lymphocytes from immune Lewis animals.

EFFECTS OF ANTIGENIC COMPETITION ON IMMUNE RESPONSES TO TUMORS

Why mammals develop cancer remains a riddle. It is a riddle because there is abundant evidence that cancers do evoke an immune response which is theoretically capable of destroying them. As a possible answer to this riddle, we propose the phenomenon of antigenic competition. In 1902 Michaelis described a phenomenon in which the immune response to one antigen was suppressed by the response to a second, unrelated antigen. Evidence of the frequency of this phenomenon has been documented in recent literature reviews by Pross and Eidinger,* T a u ~ s i g , ~ and Liacopoulos and BenEfraim.* Taussig has noted that antigenic competition occurs during varied circumstances and is probably not a single phenomenon. It can occur when the antigens are part of the same molecule or different molecules and when the antigens are administered at the same time or sequentially. We think that suppression of the immune response to one antigen, or set of antigens, by the immune response to a previously administered unrelated antigen, or set of antigens, may be a mechanism by which tumors evade detection. The experiments reported here are an attempt to determine if the single administration of a strong antigen might interfere with the immune response to tumor antigens.