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Since 1976, a double blind study has been conducted to assess the value of levamisole as adjuvant treatment to surgery for non-small cell carcinoma of the lung. Fifty-one patients were evaluable with a minimal follow-up period of 1 yr. No difference could be observed between the two groups in the duration of the survival and of the disease free survival. In cases of complete resection without any lymph node involvement, an increase of the free interval was observed. This was not statistically significant.

The influence of inosiplex upon various in vitro leucocyte assays was studied in normal individuals. It was found that the drug increases the response of bidirectional and unidirectional mixed lymphocyte cultures at concentrations of 200, 300, and 500 µg/ml. It also significantly increases the percentage of active T rosettes (concentration range: 50 to 500 µg/ml) and the percentage of autologous red cell T rosettes (concentration: 100 µg/ml). In contrast, inosiplex did not modify the percentage of total T rosettes and EAC rosettes. Inosiplex increases the number of nonadherent leucocytes in the leucocyte adherence inhibition test at a concentration range between 100 and 300 µg/ml. Finally, inosiplex also increases the percentage of monocytes phagocytizing yeast at a concentration between 50 and 500 µg/ml. These data indicate that inosiplex enhances the function of normal human T cells, monocytes, and possibly neutrophils. Therefore inosiplex appears to have immunostimulant properties.

This study reports the in vitro influence of morphine, dextromoramide, levomoramide, and methionine-enkephalin upon normal human T blood lymphocytes by using the active and total rosette tests. Morphine and dextromoramide inhibited the percentage of active T rosettes. This effect was completely reversed in the presence of naloxone, their specific antagonist. The specificity was further demonstrated by the absence of the effect of levomoramide, the inactive enantiomere, upon the rosette system. Methionine-enkephalin increased the percentage of active T rosettes. This effect was specifically inhibited by naloxone. These observations suggest that normal human blood T lymphocytes bear surface receptor-like structures for morphine, dextromoramide, and methionine-enkephalin. Such findings may provide a link between the central nervous system and the immune system.

We report the case of an African patient with acquired immune deficiency syndrome (AIDS) who had a chronic cryptococcal rectal abscess with anal fistula and a disseminated neurologic and bony fungal disease, associated with pulmonary infiltration due to Pneumocystis carinii. The anal lesion was surgically excised because of failure of the medical treatment. Although clinical intestinal cryptococcal involvement is quite rare, the experience here recorded should draw physicians' attention to the possibility of an insidious disseminated disease in AIDS patients.

A woman with a T cell lymphoproliferative malignacy and heterozhgosity at the X chromosome-linked locus for glucose-6-phosphate dehydrogenase (G-6PD) isoenzymes was studied to find the clonal origin of her circulating neoplastic T cells. The red blood cells, polymorphonuclear cells, whole mononuclear cells, and T cell-depleted mononuclear cells contained both A and B isoenzymes of G-6-PD. In contrast, the tumor cells, separated by using their capacity to form rosettes with sheep red blood cells, contained only the B isoenzyme of G-6-PD. This observation strongly suggests the monoclonality of this T cell malignancy.

Publisher Summary This chapter discusses the objectives of European Organization for Research on Treatment of Cancer (EORTC), its structure, and its activities. The aims of the EORTC are to conduct, develop, coordinate, and stimulate research in Europe on the experimental and clinical bases of treatment of cancer and related problems. Extensive and comprehensive research in this wide field is often beyond the means of the individual European laboratories and hospitals and can be best accomplished through the joint efforts of the clinical and basic research groups of several countries. EORTC has a Council that plans and supervises the activities within the organization. The Administrative Board of the Council prepares the meetings of the Council and handles the daily work involved with administrative and financial matters. EORTC has initiated four major efforts in the field of cancer treatment: a screening program of potential anti-cancer agents; the organization of clinical and preclinical cooperative groups aimed at carrying out controlled clinical trials with new therapeutic agents and regimens; the organization of collaborative research programs; the initiation of symposia, courses, and publications on the subject of cancer research and treatment.

This paper summarizes the data related to the relations between enkephalins and endorphins and the immune system. It is shown that lymphocytes have surface receptors for endorphins and enkephalins. Furthermore, endorphins and enkephalins can influence several immune functions such as antibody synthesis, lymphocyte proliferation, and natural killer cytotoxicity. It is thus possible that the receptors play a functional role. In view of these observations, several hypotheses are proposed. Endorphins and enkephalins are physiological regulators of the immune response (two-hit opioid peptide lymphocyte receptor hypothesis) and they are humoral mediators between the central nervous system and the immune system. They may play a pathogenic role in a variety of diseases with primary or secondary immunological defects. Finally, enkephalins and endorphins can be considered as immunomodulators and modifiers of the biological response and as such may become a tool in the field of immunotherapy.

The reason for giving substances with immunostimulatory properties is to restore or normalize immune functions. Since various human pathogenic viruses can induce immunodepression, the administration of immunostimulants offers a possibility for therapeutic intervention in the immune system. This could be demonstrated. Various virus infections can effectively be influenced by the synthetic immunostimulating agent Inosine Pranobex.

In an open study inosiplex, a new synthetic immunomodulatory drug, was given to 15 patients with rheumatoid arthritis (RA) 3 g daily until clinical improvement occurred and then tapered. Nine of 15 patients experienced clinical benefit evidenced by a reduction of morning stiffness, fewer tender joints, decreased proximal interphalangeal joint circumference, and decreased sedimentation rate and fibrinogen level. Three patients responded rapidly to inosiplex (in two weeks) and a clear cut improvement was noticed within 1 month by all the responders. Two patients showed an exacerbation of the disease. No toxic drug effect was noticed. Although the mode of action of inosiplex in RA appears unclear, its rapidly of action and high rate of response should encourage further study of its use in the treatment of RA.

In order to eliminate the risk of transmission of infectious diseases and of alloimmunisation, a pre-deposited autologous blood program for elective surgery has been started at the Erasmus Hospital. In 8 months, 51 patients have given 111 units of packed red cells and 111 units of fresh plasma. Two vasovagal reactions were observed. Four patients were withdrawn from the program in view of a hematocrit decreasing below 34%. Out of these 51 patients, 27 (53%) were transfused with only autologous blood. The autologous blood not distributed to these patients was given to other patients (10% of packed red cells and 24% of plasma). This pre-deposited autologous program has allowed to operate more than 50% of patients, undergoing elective surgery, only with autologous blood and to save homologous blood. The pre-deposited blood appears to be an interesting tool in transfusion safety and in the reduction of blood demand.

Twenty patients with alopecia universalis, alopecia semiuniversalis and alopecia areata were studied for their immune parameters. Fourteen of them received an oral treatment with Isoprinosine, a synthetic immunomodulator. Ten patients showed the presence of several autoantibodies. No significant abnormalities in various T cell rosette markers were found, but T4/T8 ratios tended to be elevated. Erythrocyte antibody complement (EAC) rosettes were usually decreased. Treatment with Isoprinosine produced a clinical response, as judged by total or partial hair growth, in nine of the fourteen patients treated. It was striking to observe that seven of the nine responders had autoantibodies prior to treatment. These autoantibodies disappeared or decreased with Isoprinosine therapy. In contrast, only one of five nonresponders had serum autoantibodies. After treatment, both groups showed an increase in blood-active T rosettes. These results suggest that alopecia is a heterogeneous disease subdivided by the presence or absence of autoantibodies since clinical response was mainly obtained in patients presenting autoantibodies.

Lynestrenol, a synthetic steroid progesterone-like substance, has been found to enhance the stimulation of normal human lymphocytes. It increases the phytohemagglutinin response and the mixed-lymphocyte cultures. This augmentation can, in some cases, be higher than 100% of the phytohemagglutinin or mixed lymphocyte reaction baseline. There is no significant effect on the pokeweed mitogen stimulation. It is concluded that lynestrenol can modulate, "in vitro", some T cell functions.

The interferons are known to induce the expression of cell surface determinants. Gamma interferon, in particular, has been shown to enhance class II antigens (DR) on the cell surface. We used this gamma interferon to induce beta 2-microglobulin (beta 2 mu) and a minor, sex related transplantation antigen called H-Y on the surface of B lymphoma cells. The antitumor effect of interferon could thus be at least twofold: an antiviral effect already known and an increase of intercellular recognition (by cell surface marker enhancement); allowing the tumor cells to be "seen" better by cells of the immune system.

The cellular immunity of haemodialysis and continuous ambulatory peritoneal dialysis (CAPD) patients was studied with regards to T-lymphocyte subsets and to suppressor T-cell function. The two groups of patients showed similar alterations: low proportions of suppressor-cytotoxic T-cells and low suppressive activity. In both groups there is a deterioration of this suppressive activity with time on dialysis.

T lymphocyte subsets were enumerated and suppressor cell activity was assessed in 17 CAPD patients. The lymphocyte population and function were comparable to values obtained in patients treated by hemodialysis. The poor lymphocyte function did not correlate with parameters implicated in cellular immunity alterations or with plasma concentrations of immune globulins.

A new test termed the human allogeneic rosette test (HART) is reported for the detection of small amounts of erythrocyte autoantibodies. It compares the percentage of rosettes formed around lymphocytes from normal subjects when either red cells from patients are added or autologous or allogeneic normal red cells. The HART is positive when the percentage of rosettes made with the control's red blood cells is significantly more than the percentage of those made with the patient's red blood cells. Twenty-two out of twenty-six patients with a positive antiglobulin test had a positive HART. Thirty patients with a negative antiglobulin test but with clinical or biological data suggesting an erythrocyte autoimmune disorder were also studied with the HART. Out of sixteen patients with chronic lymphatic leukaemia, ten had a positive test; all three patients with idiopathic thrombocytopenic purpura showed a positive HART; two out of three patients with cirrhosis and one out of four patients with Hodgkin's disease also had a positive test. No correlation was found between the positivity of the HART in these patients and their haematological values. Two patients with suspected autoimmune haemolytic anaemia and with a negative anti-globulin test but a positive HART were treated with steroids. Both responded very rapidly to the treatment suggesting an immune origin for the anaemia. The HART has been reproduced experimentally. Normal human red blood cells, sensitized with different amounts of either an auto-antibody or anti-D were rosetted with autologous normal lymphocytes. The results showed that the percentage of rosettes with red cells coated with small amounts of antibody was significantly less than the percentage of rosettes with uncoated red cells. A plot of these results seemed to indicate that the HART was about twenty times more sensitive than the antiglobulin test. The nature of the cells involved in the positive HART-negative direct antiglobulin test red cell binding was also analysed. They appear to be related to the T cell population. The role of the receptors for IgG in the HART was demonstrated by showing that aggregated and non-aggregated human IgG could inhibit the HART phenomenon. In conclusion, the HART appears to be a new and sensitive immunological test capable of analysing erythrocyte autoimmune disorders.

This study reports the in vitro influence of morphine, dextromoramide, levo-moramide and methionine-enkephalin upon normal human T blood lymphocytes by using the active and total rosette tests, Morphine and dextromoramide inhibited the percentage of active T rosettes. This effect was completely reversed in the presence of naloxone, their specific antagonist. The specificity was further demonstrated by the absence of the effect of levo-moramide, the inactive enantiomere, upon the rosette system. Methionine-enkephalin increased the percentage of active T rosettes. This effect was specifically inhibited by naloxone. These observations suggest that normal human blood T lymphocytes bear surface receptor-like structures for morphine, dextromoramide and methionine-enkephalin. Since non-opiate receptors have also been described on B lymphocytes, the ‘two hits opioid lymphocyte receptor hypothesis’ is presented. This theory postulates that opioid peptides can modulate the co-operation between T and B lymphocytes. Finally, such findings may provide a link betweeen the central nervous system and the immune system, and enkephalins may be the humoral mediators between the two systems.

Six patients with intradermal metastases of malignant melanoma were treated with intralesional bacile Calmette-Guérin (BCG). Four patients showed a good response with regression of injected, and in some cases, uninjected lesions, whereas two developed metastatic viscereal disease and died. Three of the six patients had complete regression of all lesions, and one exhibited complete regression of untreated lesions. All remain free of disease. The fourth patient had complete regression of injected and of some untreated lesions, but developed widespread dissemination and died. Preliminary experiments suggest the presence of a blocking factor in his sera which abrogates the lymphocyte stimulation in response to melanoma antigens. Three of four responders (i.e. those patients in whom treated lesions decreased in size by more than 50% for more than 1 month) showed a dramatic increase in lymphocyte stimulation to melanoma antigens. All responders (four out of four) had a marked increase to phytohemagglutinin (PHA), whereas non responders had no increase in lymphocyte stimulation either to melanoma antigens or PHA. Two of four responders showed inhibition of leukocyte migration to melanoma antigens before BCG, and two of four responders were positive after BCG. Of the nonresponders, one was positive and one negative before BCG; this remained the same after. There was a marked increase in active rosette forming cells in all responders and in one of the two nonresponders. Histopathologic studies at 3 hours, 6 hours, 24 hours, 14 days, and 4 weeks after BCG showed a definite sequence of events occurred, progressing from 1) inflammatory cell response at the periphery of the lesion, disruption of melanogenesis, extensive dumping of pigment from melanoma cells, proceeding to actual cell death at 24 hours, to 2) macrophages containing melanin and granulomas replacing tumor by 2 weeks. These studies suggest that BCG activates both specific and nonspecific immune responses. Thus, in vitro parameters of cellular immunity, including migration inhibitory factor production and inhibition of leukocyte migration, are affected by intralesional BCG, and some, particularly the lymphocyte stimulation and rosette test, seem to correlate with the clinical response of the patients.

Peripheral blood mononuclear cells from 15 patients with alcoholic cirrhosis (AC) and 15 matched healthy controls were tested for their proliferative response to mitogens such as PHA and con A, tumour promoter PMA and OKT3 monoclonal antibody, for their capacity to produce IL-2 and to respond to recombinant IL-2 (rIL-2). The expression of IL-2 receptor (Tac) together with two other activation markers, the receptor for transferrin (T9) and Ia antigen have also been assessed. A profound decrease of proliferative response was observed after stimulation by lectins and PMA. IL-2 production was significantly decreased (0.39 +/- 0.07 versus 0.82 +/- 0.009 units; P less than 0.001) in alcoholic cirrhosis. Resting PBMC of these patients disclosed spontaneous responsiveness to rIL-2 without requiring prestimulation with PHA as observed in healthy subjects. This abnormal response was associated with significantly increased percentages of Tac (19.4 +/- 3.1 versus 5.1 +/- 1.1%; P less than 0.001), T9 (13.6 +/- 3.3 versus 6.6 +/- 1.1%; P = 0.04) and Ia positive cells (21.4 +/- 5.4 versus 11.5 +/- 1.4; P less than 0.05) in alcoholic cirrhosis. Defective proliferative activity and impaired IL-2 production, combined with an increase of lymphocytes bearing T cell activation markers and of rIL-2 responsiveness could represent in vitro correlates for mechanisms leading to immunoregulatory disturbances in cirrhotic patients.

This paper summarizes presentations on the immunopharmacology of Isoprinosine, NPT 15392, and Azimexone made in the Therapy Communication Session: Immunopotentiators II.

The action of lynestrenol, a synthetic progesterone-like substance, was studied in Syrian golden hamsters inoculated with cells transformed by herpes simplex virus type I. Daily ip injections of 1 mg lynesterol/kg delayed tumor growth. Lynestrenol alone only slightly increased the survival of the animals. This effect was more marked when the animals were also given injections of Staphylococcus aureus Cowan A. Survivors showed an increased resistance to challenge with infected cells. Hamsters previously given injections of killed transformed cells and then challenged with living cells showed a facilitation of tumor growth. This facilitation was inhibited by lynestrenol alone or combined with S. aureus Cowan A.

This article summarizes the hematological and immunological consequences of splenectomy in children. The hematological consequences are mainly noticed in the number of white cells and platelets. Indeed, platelets can remain elevated several weeks and even several months after surgery. Rarely antiplatelets aggregant drugs will be given if the platelet count is higher than one million per cubic millimeter. The immunological consequences of splenectomy in children are mainly manifested if the surgery was performed before the age of 6 or 7. The major consequence is a rapid and often lethal infectious complication. In diseases like thalassemia major or lymphoma, there is an increased risk of infection. The immunological mechanism seems linked to a decreased antibody formation in presence of higher antibody titre needed by the reticuloendothelial system to eliminate the microorganisms responsible for the infection. Therapeutic measures can be proposed: delay the age of splenectomy, leave some splenic tissue, administration of penicillin and lastly immunization against some antigens mainly responsible of the infection.

The immune system is reviewed. Its ontogeny, differentiation and localization are discussed. Although cellular immunity mainly depends on T cells (thymus-derived) and humoral immunity depends on B cells (bone-marrow-derived), there are many interactions between these two systems. The role of T cells, in the production of antibodies, appears to be mainly regulatory. Various subpopulations of T cells are mentioned. The interactions between B cells and macrophages are described, as well as the markers of human T and B cells.

Lynestrenol, a synthetic progesteronelike drug, was assessed for its influence upon human leukocyte tests in vitro and in vivo. Lynestrenol markedly enhanced the lymphocyte response to phytohemagglutinin, the mixed lymphocyte culture, the active T-rosette test, the autologous red cell rosettes, and the number of nonadherent cells in the leukocyte adherence inhibition test. All these results indicate a stimulatory effect upon human T-cell function. Lynestrenol also increased monocyte phagocytosis. Lynestrenol delayed the appearance of malignant tumors in hamsters. Finally, lynestrenol, given to lung cancer patients, increased their T-cell functions as evaluated by skin tests. T-cell rosettes, and phytohemagglutinin response. Lynestrenol does possess immunostimulatory properties.

In order to study the influence of iron overload on the polymorphonuclear leucocyte (PMN) metabolism of patients on chronic hemodialysis, generation of superoxide anion (O2-) by PMN in whole blood was compared in two groups of hemodialyzed patients: group A consisted of twenty-one individuals with serum ferritin levels above 1000 ng/ml and group B of nineteen individuals with serum ferritin levels below 1000 ng/ml. Whereas basal production of O2- was similar in the two groups (6.3 +/- 4.6 vs 11.5 +/- 8.3 nmoles O2- 10(6) granulocytes-1 15 min-1) (mean +/- s.e.m.), PMN response to opsonized zymosan was significantly lower in group A as compared with group B (86.5 +/- 6.3 vs 120.4 +/- 8.2 nmoles O2- 10(6) granulocytes-1 15 min-1) (p less than 0.01). Superoxide anion generation induced by the dialysis procedure was reduced in eight patients from group A (89.2 +/- 32.1) as compared with eight patients from group B (374.3 +/- 100.0 nmoles O2- 10(6) granulocytes-1 15 min-1) (p less than 0.05). These data suggest that iron overload may be involved in the impairment of neutrophil phagocytosis in patients on chronic hemodialysis.

T cell subsets tested with markers for Fc receptors for Ig (TM, TG and EAhu rosettes) or monoclonal antibodies (T4 and T8 lymphocytes) were investigated both in normal volunteers and in kidney transplant recipients with a well functioning graft and receiving low immunosuppressive therapy, before and 4 hr after administration of 100 mg of hydrocortisone. Hydrocortisone induced a redistribution which was characterized by a decrease in the percentages of TM (38 +/- 2.4 before; 22 +/- 2.9 after; P less than 0.0005) and T4 (48 +/- 2.6 before; 35.8 +/- 2.7 after; P less than 0.0025) lymphocytes. Transplanted patients under chronic immunosuppression already disclosed a reduction of the percentages of TM (19.4 +/- 2.6; P less than 0.005) and T4 (41.1 +/- 3.6; P less than 0.05) lymphocytes before the administration of hydrocortisone when compared to the values obtained in normals. Moreover, significant decrease of percentages of TM lymphocytes (19.4 +/- 2.6 before; 12.8 +/- 2.6 after; P less than 0.01) were obtained after hydrocortisone injection. In contrast, T8, TG and EAhu rosettes percentages were characterized by a relative resistance to immunosuppressive agents--the only exception being TG lymphocytes in transplant recipients. It is concluded that TM and T4 depletion is a common feature of acute and chronic drug-induced immunosuppression, suggesting that helper-inducer cells are important targets for immunosuppressive therapy.

Lynestrenol, a synthetic progesteronelike drug, was assessed for its influence upon human leukocyte tests in vitro and in vivo. Lynestrenol markedly enhanced the lymphocyte response to phytohemagglutinin, the mixed lymphocyte culture, the active T-rosette test, the autologous red cell rosettes, and the number of nonadherent cells in the leukocyte adherence inhibition test. All these results indicate a stimulatory effect upon human T-cell function. Lynestrenol also increased monocyte phagocytosis. Lynestrenol delayed the appearance of malignant tumors in hamsters. Finally, lynestrenol, given to lung cancer patients, increased their T-cell functions as evaluated by skin tests, T-cell rosettes, and phytohemagglutinin response. Lynestrenol does possess immunostimulatory properties.

Human recombinant interferon-alpha 2C was given to 4 patients with essential thrombocythaemia. Three patients achieved a complete remission on day 19 +/- 1 and the 4th achieved a partial remission. After 4 weeks of induction therapy, a maintenance therapy of twice weekly intramuscular injections of 5 X 10(6) or 10 X 10(6) IU was instituted but did not maintain the remission.

Publisher Summary This chapter describes the different aspects of rosette formation. It has been shown that erythrocytes of a variety of species can adhere to frozen sections of mouse spleen. The chapter describes an early study where it was found that the adherence phenomenon on living cell spleen suspension was seen only after collagenase splenic perfusion. Neuraminidase treatment of erythrocytes removes the adherence properties, and trypsin treatment of the spleen cells inhibits binding. Human lymphocytes can rosette with Marmoset erythrocytes at 40°C. The chapter presents some evidence for genetic polymorphism in binding of erythrocytes of different marmosets. The thymic factors, transfer factors, and isoprinosine increase active E-rosette formation without increasing total T rosettes. All these drugs have the common property of stimulating some T cell functions.