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Our experiments show that lymphocytes of CLL patients, having typical B cell characteristics, form rosettes with IgM-coated bovine erythrocytes. Of 18 investigated patients, 3 to 78% (mean 29%) of the isolated lymphocytes reacted with EA-IgM. With mixed rosette assays. EA-IgM bound to cells bearing receptors for IgG as well, but not receptor-bearing lymphocytes. Rosette formation could be completely blocked by addition of IgM at concentrations as low as 0.17 mg/ml. Ten milligrams per milliliter of aggregated human IgG had no effect on the rosette formation with EA-IgM but completely abolished the binding of EA-IgG. Adult human or rabbit serum blocked the EA-IgM binding, whereas cord blood serum and FCS had no effect. These inhibition data indicate that EA-IgM binding does not occur via a somewhat altered IgG-Fc receptor but reacts with different membrane structures. That EA-IgM receptor can be cleaved off with trypsin and can be reconstituted after overnight cultivation, also supports this viewpoint. In contrast to the situation in normal subjects, in CLL patients the IgM receptors are demonstrable before overnight cultivation and are found on cells with B cell characteristics.

Patients with penicillin allergy demonstrate a T cell proliferative response after in vitro stimulation with penicillin G (Pen G) and other beta-lactam antibiotics. To understand better penicillin-allergic reactions, T cell subset stimulation with Pen G was studied and compared with other soluble (tetanus toxoid and purified protein derivative [PPD]) and membrane-bound viral (influenza A and Epstein-Barr viruses) antigens. A double fluorescence method for flow cytometry was used to evaluate the activated cells simultaneously by pyronin Y staining of RNA and by indirect immunofluorescence of cell surface T4, T8, or Leu 8 antigens. The antigens used stimulated mainly the T4+ subset (greater than 90%), whereas the number of activated T8 cells was slightly increased only in Pen G- and influenza A-triggered cultures (5% to 15%). Leu 8 antigen was used to analyze more precisely the activated T4+ cells. Pen G and influenza A and Epstein-Barr viruses stimulated both T4+, Leu 8+ (greater than 50% of activated cells, inducers for suppressor cells), and T4+, Leu 8- (helpers for B cells) subsets, whereas PPD activated mainly T4+, Leu 8- subpopulations. These results indicate that penicillin-allergic patients with skin symptoms demonstrate a T cell subset stimulation that resembles more the reaction versus viral antigens (membrane incorporated) than to soluble antigens like PPD. These results suggest that Pen G is presented to T cells like viral proteins and might thus cause allergic reactions resembling skin symptoms observed in viral diseases.

Lymphocyte subpopulations were investigated in 32 patients with malignant melanoma, 25 patients with bronchogenic carcinoma and 59 control subjects. Whereas the determination of membrane immunoglobulin-bearing lymphocytes and of complement receptor-bearing lymphocytes gave comparable results in the tumour patient and control group, significant differences were found in the T-lymphocyte population using the sheep red blood cell (SRBC) assay. The so-called "active" Wybran rosette test, which characterizes a T-cell subpopulation with an especially avid receptor for SRBC, gave significantly lower results in patients with melanoma (25% control 35%, p less than 0.01) and bronchogenic carcinoma (21% control 35% p less than 0.01). Determination of the total T-cell population using the Jondal rosette assay gave significantly lower values in the patients with melanoma (52%, control 63%, p less than 0.01), but not in those with lung cancer (65%). Low rosette values were detected even at low histological invasion levels (classified according to Clark) in the patients with melanoma. No correlation was found between the invasion level and the percentage of rosette-forming cells. The significance of these findings and the value of the rosette assay in the assessment of the immunological reactivity of tumour patients is discussed.

The effect of exogenous recombinant interleukin-2 (IL-2) or of antibody crosslinking on the activation of human T-cell subsets by IgG2a (OKT3/BMA030), IgG1 (Leu4 and UCHT1), or IgG2b (BMA031) anti-T3 antibodies (CD3) was investigated. In so-called nonresponder cultures as well as in monocyte-depleted cell cultures addition of IL-2 increased the CD3-induced activation and proliferation of T4 and T8 cell subsets. Relatively more T8 than T4 cells were stimulated by antibody binding and IL-2. Crosslinking the cell-bound CD3 antibodies by plastic bound goat anti-mouse antibodies activated both T-cell subsets optimally and increased the IL-2 production of the IgG1-CD3 stimulated cultures. The data show that T cells (T8 greater than T4) can be stimulated by CD3 antibody binding and IL-2, but that crosslinking the cell-bound CD3 antibodies is crucial for optimal T4 cell stimulation and IL-2 production.

Binding of anti-CD3 antibody BMA030-F(ab')2 to T cells is not able to induce T cell proliferation even after additional cross-linking by plastic-bound goat anti-mouse Ig antibodies (panning) and addition of either interleukin (IL) 1 or IL2. In search for agents able to complement the signals provided by BMA030-F(ab')2, several antibodies directed against CD2, CD4, CD5, CD6 and CD8 were used. Neither of these caused T cell proliferation either by themselves or when simply added together with BMA030-F(ab')2. However, if BMA030-F(ab')2 and any other of these anti-CD2, CD4, CD5, CD6 or CD8 antibodies were cross-linked, then proliferation of T cells occurred. The mitogenic effect of cross-linking BMA030-F(ab')2 and a second anti-T cell antibody is dependent on the presence of monocytes or exogenously added IL2. The enhancing effect of monocytes could not be replaced by addition of IL1, suggesting that other soluble factors or monocyte contact might be involved in induction of activation signals. The mechanism leading to this mitogenic effect is dependent on combining cross-linking of BMA030 with the second anti-T cell antibody, whereby the second antibody appears to act as an "anchor" for the CD3 antibody, controlling and/or changing the signal transduction via the CD3 structure. This "anchor" hypothesis could be substantiated by the following observations: the best stimulatory signals were obtained at a BMA030/anti-T cell antibody ratio of 1:1; the effect is independent of the antibody isotype and the epitope recognized by the second antibody; the binding of BMA030 and separate cross-linking of the anti-T cell antibody was not sufficient to trigger T cell mitogenesis; immobilization by direct binding of the CD3 antibody alone or of the CD3 and second membrane structure/antibody complex separately was not sufficient to stimulate T cell proliferation. A further interesting aspect of this finding is the fact that a selective T cell stimulation is possible, since cross-linking BMA030-F(ab')2 plus anti-CD4 antibodies induced a selective stimulation of T4 cells, while cross-linking BMA030-F(ab')2 plus anti-CD8 activated solely T8 cells. It is thus possible to selectively activate T cell subsets in vitro.

About 15-20% of human circulating T-cells express Fc-IgG receptors (TG cells), and about 70-80% have Fc-IgM receptors (TM cells). TM cell enriched fractions are functionally heterogenous cell populations. TM cells are able to mature into specific cytotoxic T-cells after mixed lymphocyte reaction; TM cell fractions also comprise the helper T-cells for pokeweed mitogen (PWM) induced B cell differentiation; and some TM cells can be induced to act suppressively on PWM induced B-cell differentiation and maturation. TG cells represent activated, relatively radiation resistant suppressor T-cells, and these cells are also active in natural cytotoxicity (NC), antibody dependent cellular cytotoxicity (ADCC) and mitogen induced cellular cytotoxicity (MICC). IgG-immune-complex interaction with the Fc-IgG receptor on TG cells modulates Fc-receptor expression as it leads to loss of Fc-IgG receptors and expression of Fc-IgM receptors on the original TG cells after culture. This modulation of surface markers is accompanied by functional changes since ADCC and suppressor cell activity is reduced following immunecomplex interaction. Fc-IgG and Fc-IgM receptor expression on human T cells seems therefore to characterize distinct functional stages of T cells. IgG immunecomplex interaction in vitro seems to be a potent tool to change the different functional stages.

Two anti-CD3 antibodies and their Fab/F(ab')2 fragments were compared with regard to their requirement for secondary signals and generations of intracellular messengers. The anti-CD3 antibody BMA030 was found to require monocyte contact to elicit T-cell mitogenesis. Cross-linking by plastic-bound goat anti-mouse antibodies (panning) failed to activate T cells, even in the presence of recombinant IL-1 or IL-2. In contrast, crosslinking of the anti-CD3 antibody Leu4 or Leu4 fragments was mitogenic in monocyte-free cultures. Measurements of intracellular Ca2+ ([Ca2+]i) and generation of inositol phosphates revealed that binding (+/- panning) of BMA030, Leu4, and their F(ab')2 fragments generated similar amounts of intracellular messengers and thus failed to explain the different responsiveness to passive crosslinking. Since the generation of these messengers was not necessarily followed by proliferation but was always observed when mitogenesis occurred, we conclude that the elevation of [Ca2+]i and the production of inositol phosphates are required but not sufficient to trigger mitogenesis.

In this paper, data are presented which indicate that receptors of human peripheral blood lymphocytes (PBL) for pig erythrocytes (PRBC) and sheep erythrocytes (SRBC) are identical or at least very similar to each other with a higher avidity of PBL for SRBC than for PRBC. As an average, 50 +/- 9% of human PBL formed PRBC rosettes (Ep), compared to 70 +/- 7% of SRBC rosettes (Es). Lymphocytes incubated with SRBC plus PRBC ('co-rosetting') formed 10 +/- 5% of mixed rosettes (Em) but no pure Ep. Resuspension of rosetted lymphocytes followed by co-rosetting with the other erythrocyte species revealed that the majority of Ep became Em, while the majority of Es remained pure Es even after co-rosetting with PRCB; no pure Ep was newly formed. Incubation at 37 degrees C abolished almost all Ep as compared to 9% Es. Anti-thymocyte serum inhibited both types of rosette formation. PBL from patients with chronic lymphatic leukemia formed only 2.5 +/- 2.5% Ep. 1.7 +/- 1.1% of PBL expressed both membranes immunoglobulins and receptors for PRBC. Trypsin treatment abolished both kinds of rosette formation almost completely, while neuraminidase treatment of erythrocytes led to a raise in Ep formation from a mean of 53% to a mean percentage of 68%. Electron microscopic investigations did not reveal differences between binding sites of lymphocytes for PRCB and those for SRBC; however, with a technique different from the conventional one, intimate contact areas were observed between lymphocytes and both kinds of red blood cells.

Two T-lymphocyte subsets develop in the thymus which differ in the expression of glycoproteins on their cell surface. About 60% of the circulating T cells express the glycoprotein T4, while about 30% have the glycoprotein T8. T4 and T8 cells can be determined in the peripheral blood or various organs with monoclonal antibodies. T4 and T8 cells differ in their antigen recognition, have different functions, and can cause various pathohistological changes. T4 cells recognize the antigen in association with the HLA-D/DR/DP determinants. Upon antigenic stimulation they liberate various factors and initiate and amplify an immune response (T4 = helper/inducer T-cells). They can also be cytotoxic and are mediating effector functions via macrophage activation. T8 cells recognize the antigen in association with HLA-A/B/C determinants. They exert their cytotoxic or suppressive effector functions mainly in viral infections. The T4 or T8 cell-mediated pathohistological changes are discussed in the light of the well studied T-cell infiltrations in lepra lepromatosa or lepra tuberculosa. The T4/T8 cell dyscrasia in the peripheral blood, described in a variety of infectious, autoimmune or immunodeficiency diseases, may be due to enhanced proliferation, selective sequestration, reduced production or the elimination of a subset. T-cell subset analysis in joints, bronchial lavages and tissues has clarified the pathomechanism in a variety of autoimmune diseases, although the etiology remains obscure. For example, in rheumatoid arthritis, multiple sclerosis, and sarcoidosis, a T4 cell-mediated reaction with macrophage activation can be found. T4/T8 cell analysis may also be of value in dissecting heterogenous diseases, e.g. systemic lupus erythematosus. Of value is also the additional demonstration of membrane components reflecting T-cell activation (IL-2 receptor or DR-antigen expression) which serves to identify the activated T-cell subset in peripheral blood. Finally, T4/T8 cell analysis can be helpful in deciding treatment, as the T-cell subsets have a different sensitivity to immunosuppressive drugs.

Lymphoblasts from 18 patients with untreated acute lymphoblastic leukemia were investigated for the presence of conventional cell surface markers (spontaneous sheep red blood cell rosette formation, complement receptors, and surface immunoglobulin). The expression of Fc receptors for both IgG and IgM was investigated using indicator bovine erythrocytes coated with rabbit anti-BRBC (IgG and LgM fractions). The leukemic cells of all patients in this tudy expressed Fc receptors for both IgC and LgM. In contrast with previous reports, null (non-T non-B) lymphoblasts as well as T lymphoblasts demonstrated Fc-IgG and Fc-IgM receptors. However, these two immunologic subclasses of leukemic cells demonstrated significantly different patterns of Fc receptor distribution. These data suggest that expression of Fc receptors is an early event in cellular differentiation in this lymphoid malignancy.

In this study, we investigated whether the phenotype-related differentiation of human 2H4+ (CD45R) naive cells to 2H4- (CDw29) memory CD4 cells corresponded to modulation of interleukin (IL) 2, IL 4, interferon (IFN)-gamma and granulocyte-monocyte colony-stimulating factor (GM-CSF) gene expression, a phenomenon which might correlate to the distinct functional activities of naive cells or memory cells. To mimic in vitro CD4 T cell subset differentiation, freshly isolated 2H4+ and 2H4- CD4 cells were stimulated with the anti-CD3 antibody (Leu-4), expanded in IL 2-containing medium and restimulated with Leu-4 after 7 and 13 days. Absence of monocyte-T cell interaction was compensated by adding monocyte supernatant to the culture medium and by cross-linking the anti-CD3 antibodies with goat anti-mouse antibody coated on culture dishes. It has been previously shown that in vitro stimulated 2H4+ cells acquire CDw29 surface antigens. Measurement of lymphokine gene expression by dot-blot hybridization revealed that although stimulated 2H4+ cells proliferated less than stimulated 2H4- cells, and expressed less actin mRNA, they expressed more IL 2 but less IL 4 and GM-CSF than 2H4- cells. No significant difference was observed between the two subsets for the expression of IFN-gamma. If subsets were restimulated with Leu-4 antibodies, expression of IL 2 was decreased and expression of IL 4 was increased in both subsets; however, the differences among the subsets persisted. They were even more enhanced for IL 2 but less pronounced for GM-CSF. Thus, in spite of phenotype conversion, CD4 T cell subsets maintained a distinct capacity to express IL 2 and IL 4 genes.

Two male patients with hypogonadism and four female patients who received an anti-androgen as contraceptive (cyproteronacetate) and who had recurrent angioedema are described. In one male patient, augmentation of the plasma androgen level resulted in disappearance of symptoms. In the four female patients, recurrent angioedema and urticaria developed after initiation of the anti-androgen treatment. Cessation of cyproteronacetate and a change to another contraceptive resulted in complete resolution of the previously frequent angioedematous attacks. The women are still symptom free after more than 60 patient's months. These cases suggest that an androgen deficit due to either hypogonadism or to anti-androgen treatment may be another cause of angioedema. One of the two male patients was untreated and presented with 40% normal value of C1-INH. Androgen therapy normalized C1-INH concentration in this male patient. Functional C1-INH in the same patient, studied before and after the beginning of androgen therapy, clearly increased when assessed by inhibition of amidolytic activity of C1-esterase. The other male patient with hypogonadism had already been under androgen treatment for 4 years and had C1-INH levels in the normal range. In the female patients, complement profiles were normal before and after cessation of anti-androgen contraception; however, the C1-INH plasma levels were higher after cessation of anti-androgen anticonception. These results indicate an effect of androgen deficit on the level of C1-INH in circulating plasma but do not prove a role of C1-INH in angioedema associated with diminished androgen plasma levels.

In so-called responder cell cultures--able to be stimulated by mouse IgG1 anti-T3 antibodies (IgG1-CD3)--the proliferation, IL 2 secretion and IL 2 receptor expression were lower in IgG1-CD3 than in IgG2a-CD3-stimulated cultures. Using a double-fluorescent technique, we found that IgG1-CD3 antibodies stimulate fewer T4 cells, but the same amount of T8 cells, than IgG2a-CD3 antibodies. The suboptimal T4 cells stimulation could be enhanced by adding exogenous IL 2 or by crosslinking the IgG1-CD3 antibodies by plastic-bound goat anti mouse IgG antibodies. Following antibody-mediated crosslinking, high IL 2 levels could also be found in IgG1-CD3-stimulated cultures. We conclude that CD3 antibodies of the mouse IgG1 isotype stimulate fewer T4 cells, due to insufficient crosslinking by monocytes and that T3 structure crosslinking is essential for optimal IL 2 production and secretion.

Purpose: It has become evident in the past few years that amiodarone, a powerful antiarrhythmic agent, induces considerable side effects. These may be due to an amiodarone-elicited lipid storage disease and to the iodine content of amiodarone, but might also be causally related to amiodarone-induced immune reactions. The latter possibility prompted us to develop a sensitive anti-amiodarone antibody detection assay based on the immunodot technique., Patients and Methods: Sera were obtained from 10 untreated control subjects and 33 patients receiving amiodarone. Using serum dilutions of 1:500 and 1:1,000, the lower detection limit was 0.3 microgram/ml of anti-amiodarone antibodies as calculated from a simultaneously performed IgG standard curve., Results: Screening of sera from the untreated control subjects and amiodarone-treated patients revealed that the untreated subjects had no anti-amiodarone antibodies, that only one of 16 patients without clinical side effects had elevated anti-amiodarone antibodies, but that seven of 12 patients with amiodarone-induced thyroid disease and four of five patients with other side effects had elevated anti-amiodarone antibody titers (1.2 to 2.5 micrograms/ml). The combined evaluation of anti-amiodarone antibody titers and cumulative dose was found to be a highly reliable indicator of side effects, as all patients with more than 100-g cumulative dose of amiodarone and more than 0.6 microgram/ml of anti-amiodarone antibodies had side effects., Conclusion: The detection of anti-amiodarone antibodies in patients with amiodarone-elicited side effects underscores the possible contribution of immunologic reactions to the development of certain side effects.

Phenotypic, functional and clinical analysis of two patients with Sezary Syndrome are presented. Both patients had an elevated lymphocyte count with the helper/inducer cell phenotype by analysis with monoclonal antibodies (OKT3+, T4+, T6-, T8-, M1-), had the characteristic cerebriform nucleus of Sezary cells, and were Fc-IgG receptor negative. The functional tests revealed no proliferative, cytotoxic or immunoregulatory activity of patient E.P.'s leukemic cells, while the lymphocytes of patient A.N. responded to mitogen stimulation and had helper cell capacity in pokeweed mitogen driven B cell differentiation and maturation. Both patients presented skin involvement, pruritus, hepatomegaly and patient E.P. showed generalized lymphadenopathy. The spleen size of patient A.N. was below the normal range with an estimated spleen weight of approximately 160 g (normal 180-229 g). Patient E.P. had an extremely small spleen size with an estimated weight of approximately 20 g as shown by abdominal sonography and spleen scintigraphy and had Howell-Jolly bodies within the erythrocytes. The size of the spleen in various other diseases with T cell proliferations is discussed with respect to the possible proliferative centers of the various T-cell subpopulations.

Hodgkin's disease was found in five members of the same generation in a large Swiss family. At presentation, the patients were between 20 and 30 years old. The histological diagnosis was confirmed in three patients. In one woman the differential diagnosis of histiocytic non-Hodgkin's lymphoma was considered. The patient history did not provide any conclusive evidence for environmental factors shared by all patients. Three siblings had grown up in the same household. They had never been in contact with the other pair of affected sisters. No clustering of cases in time occurred, as individual cases were diagnosed at least two years apart. Antibodies against Epstein-Barr viral capsid antigen were found in four patients (IgG: 1:10 to 1:160). There was no single HLA-haplotype common to all patients. However, two affected sisters were HLA-identical (paternal haplotype: Aw24(9), Bw62(15), DRw6; and maternal haplotype: A2, B7, DR2). Their brother with Hodgkin's disease was homozygous for A-, B- and DR-antigens. He shared all these antigens with his two affected sisters (A2, Bw62(15), DR2). A genetic predisposition in combination with environmental factors, in particular subclinical Epstein-Barr virus infection, may have been responsible for the development of Hodgkin's disease in this family.

The anti-CD3 antibody BMA030 (IgG2a isotype) induces T cell activation and proliferation if an interaction with monocytes is provided. In contrast to other anti-CD3 antibodies, it is unable to induce interleukin (IL)2 responsiveness through cross-linking by plastic-bound goat anti mouse Ig antibodies (panning). Cross-linking BMA030 with a second anti-T cell antibody is, however, able to induce IL 2 responsiveness in monocyte-depleted T cell cultures. In this report we show that a large number of different antibodies are suitable for this dual antibody stimulation, and that the extent of proliferation corresponds to the percentage of T cells expressing the respective T cell antigen. Proliferation induced by low concentrations (0.1-1 ng/ml) of other anti-CD3 antibodies requires also cross-linking with second anti-T cell antibodies. The proliferative response of monocyte-depleted T cells to two cross-linked anti-T cell antibodies plus added IL 2 is of the same magnitude as the one induced by anti-CD3 antibodies plus monocytes. On the other hand, if monocytes are present, soluble anti-CD2, -CD4, -CD8, -LFA-1 antibodies (IgG1 or F(ab')2 fragments) can inhibit OKT3 or BMA030-induced T cell activation. Anti-CD6 antibodies do not interfere with this monocyte-dependent T cell stimulation. We conclude that dual antibody stimulation mimics the physical contact of T cells with monocyte membranes, where the T cell receptor CD3 complex is cross-linked with neighboring structures (mainly so-called adhesion molecules) through the interaction with respective counter-structures on monocyte membranes. Dual antibody cross-linking bypasses this interaction and can be used to stimulate IL 2 responsiveness of antibody-defined T cells.

Eight patients with arthritis (seven with rheumatoid, one with psoriatic arthritis) were treated for 7 d with a daily injection of 10 mg of mouse monoclonal anti-CD4 antibodies (three with VIT4, five with MT151). With the exception of a short-lasting low-grade fever in one patient, no side effects were observed. Clinical symptoms (morning stiffness, number of swollen joints, pain assessment and Ritchie articular index) improved in all patients within 7 d of treatment. Improvement lasted from 3 weeks to greater than or equal to 5 months (mean approximately 11 weeks). Rheumatoid factors, immune complexes and other laboratory parameters did not change during or after treatment. Skin reactivity to recall antigens was suppressed in four out of six patients during treatment but returned to pretreatment levels within 6 weeks. Immunofluorescent analysis revealed a short-lasting drop of T cells, mainly of the CD4+ CDw29+ subset, but monocytes were also affected. The injected antibody was detectable on circulating cells for about 10 h. Within 20-24 h, the cell distribution returned to pretreatment levels. In six out of eight patients an anti-mouse-Ig response was seen. We conclude that mouse anti-CD4 monoclonal antibody (MoAb) treatment is well tolerated and that the cellular immunological changes observed are short-lasting. The low incidence of side effects may justify further clinical studies to evaluate the clinical efficacy of such treatment.

In treating rheumatoid arthritis (RA) patients with anti-CD4 antibodies (MT151 10 mg/day, 7 d) we observed diminished skin-test response to recall antigens and reduced proliferative response to antigens and mitogens (in vitro) 2-4 h following the injection. To investigate whether this diminished response is due to functional impairment of CD4+ cells, we analyzed the proliferative response of CD4+ cells to various stimuli, in conditions where the CD4 structure was either cross-linked or not. We found that in vivo anti-CD4-antibody-coated cells could be induced to proliferate if the anti-CD4 antibody was cross-linked with an anti-CD3 antibody [BMA030-F(ab')2] added in vitro and per se non-mitogenic. Also, without cross-linking the cell-bound anti-CD4 antibodies, no impairment of the proliferative capacity of CD4-antibody-coated cells could be detected; double fluorescence analyses of phytohaemagglutinin (PHA)- or CD3-stimulated cells showed that a similar proportion of CD4+ cells proliferated before and after anti-CD4-antibody treatment. The diminished proliferation observed following anti-CD4 treatment correlated to the reduced number of CD3+ and CD4+ cells in culture, which suggests that altered cell distribution might be one factor contributing to the impaired immune response.

Eleven monoclonal antibodies, directed versus the T8 glycoprotein, were compared using enzyme digestion, phylogenetic comparisons, cross-blocking of antibody binding, and blocking of specific cell-mediated lympholysis (CML). It was found that none of the 11 anti-T8 antibodies tested define the same epitope on the T8 glycoprotein. Some of these antibodies react, however, with closely related structures, as shown by cross-blocking of antibody binding and similar enzyme sensitivity of the epitopes. Moreover, these structural related epitopes show a similar involvement in the effector phase of CML reactions, since the antibodies to these neighboring epitopes inhibit the same CML reactions. Thus, it is possible to apply structural and functional criteria to define "regions" on the T8 glycoprotein, some of which are consistently involved in CML reactions, some never, and some of these regions appear to be involved in specific effector-target cell combinations only.

The immune response and the ensuing inflammation relies on a complex interaction of cells and mediators. Various drugs can interfere with individual steps of the immune response, and in so doing they often imitate regulatory mechanisms of the immune system itself. The immunosuppressive effect of corticosteroids is based on changes in cell migration, reduced responsiveness of monocytes/macrophages to various stimuli and diminished production of interleukin-2. Cyclosporin A appears to block prolactin binding to prolactin receptors on lymphocytes, thus interfering with the immunostimulatory effect of prolactin. It also appears to have a Calmodulin antagonism and might thus block lymphokine production. Anticoagulants may block delayed type hypersensitivity reactions, since activation of the coagulation cascade is involved in this type of immune reaction. Attempts to use calcium channel blockers as immunosuppressive agents, or to take advantage of the immunoregulatory effects of adrenergic substances/blockers or other neurotransmitters, are of experimental value only.