The unusual anti-mouse immunoglobulin (Ig) sensitization of a renal allograft recipient who was treated prophylactically with the anti-T cell monoclonal antibody OKT3 (IgG2a) is reported. Whereas in most patients, the injection of OKT3 (5 mg/day, i.v. for 13 days) induces the rapid appearance of neutralizing anti-OKT3 antibodies, the patient reported here did not show the signs of conventional anti-OKT3 sensitization. High levels of circulating OKT3 persisted and no OKT3+ lymphocytes reappeared during the whole treatment period. Moreover, no IgG or IgM anti-OKT3 antibodies were detected at any time, using a specific enzyme-linked immunosorbent assay. However, an atypical anti-isotype response was evidenced in this subject whose Ig were shown by indirect fluorescence to bind to normal T cells coated with OKT3 or with other anti-T cell murine monoclonal antibodies carrying the IgG2a isotype (no reactivity was observed with IgG1 or IgG2b molecules). The patient's Ig did not bind to normal T cells coated with F(ab')2 fragments of OKT3 and did not inhibit the binding of OKT3 to its target antigen indicating that they reacted with the Fc fragment of the OKT3 molecule. Additionally, and probably explained by this unusual anti-OKT3 response, the patient's Ig were shown to inhibit the phytohemagglutinin-induced proliferation of normal lymphocytes, to bind under selected in vitro conditions to normal T cells and lastly to enhance the antigenic modulation induced in vitro by OKT3 on its membrane receptor.

Antibodies, Monoclonal↗

PubMed1984

The clinical use of monoclonal anti-T-cell antibodies.

Monoclonal anti-T-cell antibodies are progressively replacing other T-cell markers in clinical immunology. A number of problems persist however, that urge for caution in interpreting the data issued from their in vitro use. Several antibodies directed against the same molecule may give different results according to the subject (due to genetic variants) or according to stage T-cell differentiation. The expression of antigenic determinants (epitopes may vary under the effect of drugs, positively (cimetidine, thymic hormones) or negatively (indomethacin). Lastly the correlation between phenotype and function of T-cell subsets may be very poor in the same pathological settings. In spite of these pitfalls, monoclonal anti-T-cell antibodies have proven to be very useful in several circumstances. Thus, in renal allograft recipients immunological monitoring with monoclonals helps the diagnosis of rejection in patients treated with conventional immunosuppression and permits early detection of antigenic modulation and xenosensitization in patients treated with the anti-T-cell OKT3 antibody.

Antibodies, Monoclonal↗

PubMed1984

T cell subset modulation of immunoglobulin production in IgA nephropathy and membranous glomerulonephritis.

Monoclonal antibodies directed against T cell subset antigens have been used to deplete peripheral blood human mononuclear cells from helper (OKT4+) and suppressor/cytotoxic (OKT8+) cells. Unfractionated cells and depleted cells were assayed for their capacity to modulate pokeweed mitogen (PWM)-driven IgG, IgA, and IgM production by autologous B lymphocytes. Immunoglobulin production in the presence of these various cell preparations paralleled the OKT4+/OKT8+ ratio defining the population. Importantly, there was no clear relationship between the level of PWM-driven Ig production by unfractionated cells and their initial relative content in OKT4+ and OKT8+ cells. Patients with IgA nephropathy and membranous glomerulonephritis showed a statistically significant increase of OKT4+/OKT8+ ratio, suggestive of suppressor T cell deficiency. There was no increase in IgA production in patients with IgA nephropathy, even in those showing high serum IgA level. A special feature found in patients with IgA nephropathy, irrespective of OKT4+/OKT8+ ratio in unfractionated cells, was a particularly intense enhancement of IgA production after OKT8+ cell depletion in some of the patients, contrasting with a particularly low effect of such depletion on the synthesis of all Ig classes in other patients. In patients with membranous glomerulonephritis there was no obvious abnormality in the modulation of Ig production by T cell subsets, with the exception of a weak suppressor activity with respect only to IgM production in a significant number of patients.

Adolescent↗

PubMed1984

Nonsteroid antiinflammatory agents as a substitute treatment for steroids in ATGAM-treated cadaver kidney recipients.

A nonsteroid antiinflammatory agent (Ibuprofen) was used in a controlled randomized study to determine its ability to replace steroids in the prophylaxis of cadaveric kidney rejection. Thirty-three cadaver kidney recipients were randomly assigned either to a control group (16 patients) receiving azathioprine, high doses of prednisolone, and antithymocyte globulin (ATGAM) for three months, or to an experimental group (17 patients) receiving azathioprine and ATGAM according to the same protocol, ibuprofen instead of steroids. The frequency of rejection was higher in the experimental group (2.18 episodes per patient) than in the control group (1.44 episodes per patient). Nevertheless, in the experimental group 5 patients had no early rejection episode, 60% of early rejections were totally reversible without steroids, and 3 patients never received steroids at all during the first year and had normal renal function and biopsies. Steroids had to be introduced in the treatment of 14 patients, but after an average period of 32.5 days after surgery OKT3+ cell level was higher in the experimental group than in the control group, but similar to the OKT3+ cell level of patients receiving conventional therapy without ATGAM. Whatever the type of treatment, an increase in the OKT4+/OKT8+ ratio was associated in most cases with increased serum creatinine values. Conversely, a decreased OKT4+/OKT8+ ratio associated with renal failure was found in cases showing biological evidence of cytomegalovirus infection.

Adult↗

PubMed1984

The mechanisms of inhibition of human IL 2 production. II. PGE2 induction of suppressor T lymphocytes.

In vitro and in vivo experiments indicate that the production of interleukin 2 (IL 2) by T lymphocytes is critical for the development of the effector phase of immunity. Complex cellular interactions are involved for the induction of IL 2 production. We have shown in a previous study that in humans monocytes can transmit opposite signals to the IL 2-producing cells. In addition to the positive signal delivered through the release of interleukin 1, human monocytes can deliver a negative signal through the release of prostaglandin E2 (PGE2). This monokine, known to activate suppressor mechanisms in several systems, was shown to inhibit IL 2 production. The data presented in this paper show that this PGE2-dependent inhibition is strictly dependent upon the presence of radiosensitive T cells in the culture, suggesting that PGE2 induces the activation of suppressor T cells modulating IL 2 production. Kinetics experiments indicate that these suppressor cells are radiosensitive during their induction phase but become radioresistant after 18 hr of incubation in the presence of PGE2. Successful in vitro induction of suppressor cells by incubation of enriched T cells with PGE2 was decisive for the analysis of the phenomenon. The induced suppressors were capable of inhibiting IL 2 production by fresh autologous T cells as well as inhibiting PHA proliferative response by these cells. A quantitative evaluation of IL 2 receptors on PGE2-treated cells has indicated that this absorption capacity was similar to the capacity of PBL known to express a low number of IL 2 receptors, thus excluding a suppression via absorption or competition for IL 2. No detectable killing of IL 2-producing cells by PGE2-induced suppressors was observed. The OKT4 and OKT8 phenotype of suppressor cells was examined. T cells were purified at two stages of differentiation before or after induction by PGE2 in vitro treatment. We conclude from these experiments that PGE2 activates suppressor cells among precursors segregating predominantly with the OKT8 subset and fewer cells with the OKT4 subset. After differentiation, however, the suppressor cells segregate with the OKT8 subset only. Such results were obtained by using positive selection (cellular affinity columns) and negative selection (monoclonal antibodies plus complement).

Absorption↗

PubMed1983

[Therapeutic use of monoclonal antilymphocyte antibodies].

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Antibodies, Monoclonal↗

PubMed1983

Reactivity of histiocytosis X cells with monoclonal antibodies.

Histiocytosis X cells were demonstrated to react with T6 antigen as well as with the M1 and I1 markers of monocytes using immuno-electron microscopy and double labeling immunofluorescence technique. The data confirm the close relationship existing between histiocytic X cells, Langerhans cells and dendritic cells, and suggest to consider the T6 antigen either as an early differentiation marker of thymocytes or as a functional marker of Mononuclear Phagocyte System subpopulations.

Antibodies, Monoclonal↗

PubMed1983

Interest in and limitations of monoclonal anti-T-cell antibodies for the follow-up of renal transplant patients.

The OKT series of anti-T-cell monoclonals has been used on 442 occasions in 41 renal allograft recipients in a 6-12 month follow-up study. Standard immunosuppressive therapy (including antithymocyte globulin in 26 patients) tended to decrease the helper-inducer/suppressor-cytotoxic cell ratio (OKT4/OKT8). Conversely, 71% of 35 renal failure episodes were associated with increased OKT4/OKT8 ratios. Twenty-three percent of renal failure episodes were associated with dramatically decreased OKT4/OKT8 ratios. At least half of these cases could be explained by a cytomegalovirus infection. In fact, similar infections were found in 6 out of 17 patients with low OKT4/OKT8 values in the absence of renal failure. These results prompt us to use anti-T cell monoclonals for the diagnosis of rejection because only nine episodes of transient increase in the OKT4/OKT8 ratio were observed in the absence of rejection. The interest of this new method for the immunological follow-up of transplanted patients is, however, limited by the difficulty in interpreting a significant percentage of tests because of (1) the presence of doubly labeled cells (OKT4+OKT8+) or the significant discrepancy between the number of OKT3+ cells and total cells labeled with OKT4 and/or OKT8 antibodies; (2) gross lymphocytopenia--most often observed in patients receiving antithymocyte globulins plus steroids; and (3) the clinically unexplained shifts in the T cell subset ratios mentioned above.

Antibodies, Monoclonal↗

PubMed1983

T cell subpopulations defined by monoclonal antibodies in autoimmune hemolytic anemia.

T cell subsets were studied using monoclonal anti-T cell antibodies in 10 patients with IgM cold agglutinins and 30 patients with IgG warm autoantibodies. Two of the 10 patients with cold agglutinin disease had abnormally low helper/suppressor T cell ratio. In the 30 patients with IgG warm autoantibodies this ratio was abnormally low in 7 and abnormally high in 7 other patients. Treatment by steroids or immunosuppressive agents tended to decrease OKT4/OKT8 ratio since high ratios were essentially found in untreated patients. This report documents the high incidence of T cell imbalance in autoimmune hemolytic anemia due to IgG warm autoantibodies and comments on its significance in the light of the great heterogeneity of this syndrome.

Adolescent↗

PubMed1982

[In vivo induction of antigenic modulation in man by an anti-T cell monoclonal antibody (author's transl)].

The anti-T cell monoclonal antibody OKT3 was administered to renal allograft recipients. A dramatic depletion of peripheral T cells was immediately observed followed, after 2-5 days, by the reappearance of a limited but significant number of or OKT3-4+ or OKT3-8+T cells showing antigenic modulation of the OKT3-defined antigen. These cells recovered the OKT3 receptor after overnight in vitro incubation.

Antibodies, Monoclonal↗

PubMed1982

Human in vivo antigenic modulation induced by the anti-T cell OKT3 monoclonal antibody.

The anti-pan T cell monoclonal antibody OKT3 was administered daily for 2 weeks in four human renal allograft recipients. The antibody induced a dramatic and immediate depletion of peripheral T cells followed by an in vivo antigenic modulation of the OKT3-defined membrane antigen: after three injections, OKT3-treated patients showed a limited but significant number of OKT3- cells of T cell nature (as defined by OKT4 and OKT8) which recovered the OKT3 receptor after an overnight in vitro incubation in the absence of the monoclonal antibody.

Antibodies, Monoclonal↗

PubMed1982

Regulatory T cell-subset imbalance in chronic active hepatitis.

Three monoclonal anti-T-cell antibodies, specifically directed against total T cells (OKT3), inducer-helper T cells (OKT4) and suppressor/cytotoxic T cells (OKT8), were used in this study to analyze peripheral T-cell subsets in hepatitis B surface antigen (HBsAg)-positive and -negative chronic active hepatitis (CAH) patients. Results showed that a clear-cut difference exists in the distribution of peripheral T cells of these two groups of subjects. HBsAg-positive CAH patients had a numerical predominance of peripheral T lymphocytes expressing the characteristics of cytotoxic/suppressor T cells. In contrast, patients with "autoimmune" HBsAg-negative CAH exhibit a predominance of OKT4 cells, namely, the helper-inducer T-cell subset. In addition, high numbers of circulating double labeled cells (expressing both the OKT4 and the OKT8 xenoantigens) were detected in some of the HBsAg-positive and HBsAg-negative CAH patients studied.

Adult↗

PubMed1982

The effects of immunomodulation on peripheral T cell subsets.

Monoclonal antibody assays were employed to monitor modifications induced in human peripheral lymphocyte subsets by thymectomy or the administration of a series of immunomodulating drugs: synthetic thymic factor, cimetidine or various combinations of anti-thymocyte globulin, azathioprine and steroids. In patients with myasthenia gravis, thymectomy produced a gradual progressive decrease in the elevated OKT4/OKT8 ratios associated with this disease until normal ratios were achieved after one year. Administration of synthetic thymic factor to three immunodeficient children for one month produced increased serum IgA levels accompanied by a normalization of proportions of total T cells and T cell subsets. Four of five uremic patients receiving cimetidine exhibited a marked increase in the percentage of OKT8+ T cells observed in subsequent blood samples with a concomitant increase in immature (OKT4+, OKT8+) lymphocytes that suggested an increase in release of such lymphocytes from the thymus. Assessment of 29 longterm renal allograft recipients by repeated T cell monitoring over an extended period of time confirmed the findings of other investigators that an increase in the OKT4+/OKT8+ ratio was predictive of subsequent allograft rejection episodes while subnormal OKT4+/OKT8+ ratios were indicative of possible cytomegalovirus or herpes virus infections.

Animals↗

PubMed1982

Immunomodulation of T cells by thymic hormone and monoclonal anti-T cell antibody.

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Animals↗