Clinical use of OKT3 for the treatment of ongoing rejection episodes has already been demonstrated as being highly effective. This work shows for the first time that combining azathioprine and OKT3 was able to delay as well as to decrease both the intensity and the quality of the anti-OKT3 immunization, allowing a 1-month prophylactic use of the MoAb. It also proves that OKT3 used prophylactically during one month can lead to 4-year first cadaver graft and patient survival rates better than those ever reported with any other immunosuppressive regimen. These results were obtained with lower doses of steroids and other immunosuppressive agents than in conventionally treated control patients. After the first two injections of OKT3, tolerance was perfect allowing out-hospital administration, and side effects consisted only in an increased number of viral infections instead of the bacterial infections observed in the conventional treatment groups. The prophylactic use of OKT3 should give even better results if it were possible to reach a 1-month administration schedule in all patients by modulating the dose of OKT3 according to the T3+ cell count and the monitoring of serum OKT3 levels.

Antibodies, Monoclonal↗

PubMed1987

Human antibody response to antilymphocytic preparations in renal transplant patients.

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Antibodies, Monoclonal↗

PubMed1987

Successful graft-versus-host disease prevention without graft failure in 32 HLA-identical allogeneic bone marrow transplantations with marrow depleted of T cells by monoclonal antibodies and complement.

Thirty-two patients with acute leukemia, chronic granulocytic leukemia, or multiple myeloma received a T lymphocyte-depleted HLA-identical marrow. After being treated with pan-T monoclonal antibodies (MoAbs) and one round of baby rabbit complement, the mean percentage of T cell depletion was 94% +/- 4%. The number of residual viable T cell infused to the patient was 0.99 +/- 0.65 X 10(6) per kg body weight. The patients were conditioned with fractionated total body irradiation (TBI) (12 Gy) preceding high doses of cyclophosphamide (120 mg/kg). Methotrexate was used as an additional immunosuppressant in the first ten patients. For the following 22 patients no posttransplant immunoprophylaxis was administered. Eight patients died within three months due to complications related to transplantation. Engraftment was achieved in all evaluable patients, and no patient has a late graft failure. The proof of total chimerism was established in 24 patients. Twenty-four of 27 evaluable patients (88%) did not have an acute graft-v-host disease (GVHD) greater than grade 0 to 1. Two patients had a grade 2 (skin only), and one patient had a grade 4 acute GVHD (the latter had only 80% of T cell depletion). A medullary relapse occurred in 11 patients (nine of them had previously been defined as "high risk leukemia"). Our data suggest that it may not be necessary to deplete nearly all T cells to prevent acute GVHD in recipients of HLA-identical marrow.

Adolescent↗

PubMed1987

Increase in blood-brain barrier permeability by altitude decompression.

Previous studies indicated that exposure to compression-decompression increases blood-brain barrier (BBB) permeability to vital dyes and antibiotics. This report concerns functional and ultrastructural BBB changes induced by altitude decompression. A 2% trypan blue solution was intravenously injected (4 ml.kg-1) into 29 experimental and 19 control rabbits. Some animals also received horseradish peroxidase. The experimental animals were subjected to 30,000 ft (4.3 psi) for 45 min. Controls were kept at ground level. The animals were sacrificed 90 min postinjection. Gross and microscopic examination and spectrophotometric dye determination revealed significantly greater tracer penetration in experimental brains (mean dye concentration 27.06 +/- 4.42 micrograms.g-1) than in controls (4.52 +/- 1.52 micrograms.g-1). No sex differences were noted. Electron microscopy suggested that the increased BBB permeability was due to transendothelial vesicular transport and, occasionally, to penetration through interendothelial junctions. These observations may have relevance to pharmacotherapy in space and at high altitudes and to the pathogenesis of altitude decompression sickness.

Altitude Sickness↗

PubMed1986

Antibodies to thymopoietin following implantation of paper disks derivatized with synthetic Cys-thymopoietin.

A synthetic peptide corresponding to Cys-thymopoietin 28-39 was synthesized and coupled by diazo linkages to aminophenyl thioether-derivatized paper disks. Disks were implanted in the peritoneal cavities of mice, initially after soaking in complete Freund's adjuvant and subsequently, at 3 week intervals, without further treatment. After four implantations, 6/6 mice developed antibodies reacting with the synthetic peptide and with native thymopoietin. In contrast, mice conventionally immunized with peptide alone (six mice) or with peptide complexed with thyroglobulin (six mice) all failed to develop antibodies. Mice immunized with disks derivatized with Cys-thymopoietin 9-20, corresponding to the other hydrophilic region of thymopoietin, also failed to develop antibodies. Thymopoietin 28-39 corresponds to an antigenic hydrophilic region of thymopoietin that contains the pentapeptide active site (thymopoietin 32-36, Arg-Lys-Asp-Val-Tyr).

Animals↗

PubMed1986

Immunoreactive thymopoietin in the mouse central nervous system.

A thymopoietin-immunoreactive substance (TP-IRS) has been detected in homogenates of mouse spinal cord and brain using a radioimmunoassay; levels were maximal at birth. TP-IRS was also detected in supernatants of mouse neuroblastoma (NIE-115) and primary spinal cord cultures but not human astrocytic and meningeal tumors or mouse primary astrocyte cultures. With affinity purified rabbit anti-TP globulin, immunofluorescent staining was seen in mouse spinal cord cultures in association with nuclear membranes of neurons and, to a lesser degree, flat background cells. From supernatants of NIE-115 cells grown in tritiated leucine and lysine, proteins of approximately 8000 and 4500 Da were isolated by TP affinity chromatography (compared with 5562 Da for thymic thymopoietin). When injected into mice, these neural proteins partially blocked neuromuscular transmission in a manner similar to thymic thymopoietin.

Animals↗

PubMed1986

Restriction of the human in vivo immune response against the mouse monoclonal antibody OKT3.

The murine monoclonal antibody OKT3 (IgG2a) was administered prophylactically to 17 renal allograft recipients (5 mg/day, i.v.), either alone or in association with corticosteroids (0.25 mg/kg/day) and azathioprine (3 mg/kg/day). In all patients the kinetics of the IgM and IgG anti-OKT3 response was monitored by means of immunofluorescence and ELISA. All patients treated with OKT3 alone showed a rapid and strong sensitization that completely neutralized the therapeutic effectiveness of the monoclonal antibody. The anti-OKT3 sensitization was manifested by accelerated OKT3 clearance and abrupt reappearance of circulating OKT3+ cells before the end of treatment. This immune response was significantly delayed and reduced in its incidence and intensity in patients receiving low dose corticosteroids and azathioprine in association to OKT3; mainly IgM anti-OKT3 antibodies that did not accelerate OKT3 clearance were then observed. The fine specificity of the antibodies produced was studied, using patients whole sera and various mouse IgG2a-affinity chromatography-purified serum fractions. The results obtained showed that the anti-OKT3 response was remarkably restricted to two main categories of antibodies: a) anti-idiotypic antibodies that inhibited OKT3 binding to T cells and abrogated its therapeutic activity and b) anti-mouse IgG2a (anti-isotypic) antibodies that did not neutralize OKT3 immunosuppressive activity. These results suggest that OKT3-immunized patients might still be sensitive to the immunosuppressive effect of other anti-T cell monoclonals that do not share the OKT3 idiotype and possibly isotype.

Animals↗

PubMed1986

The human immune response to the OKT3 monoclonal antibody is oligoclonal.

The availability of highly specific and homogeneous antibodies to human T cells by the hybridoma technique has elicited new interest in the clinical use of antibodies to lymphocytes as immunosuppressive agents. OKT3 is the murine monoclonal antibody that has been the most widely used in clinical transplantation to induce immunosuppression. This antibody recognizes a membrane molecular complex, exclusively present on mature human T lymphocytes, which is tightly linked to the T-cell antigen receptor. The long-term therapeutic use of murine monoclonal antibodies in vivo is hampered by the intense antibody response that occurs in most human patients. Thus, when administered alone, OKT3 manifests its immunosuppressive activity only during the 10 to 15 days that precede the onset of sensitization. The results presented here show, by use of isoelectrofocusing, that the antibody response to OKT3, already reported to be restricted in its specificity (only anti-isotypic and anti-idiotypic antibodies are produced), is in addition oligoclonal. This restriction of the anti-monoclonal response may suggest that an efficient way to circumvent the sensitization problem would be to administer consecutively different monoclonal antibodies presenting the same specificity but distinct idiotypes.

Antibodies, Monoclonal↗

PubMed1986

Tripeptide structure of bursin, a selective B-cell-differentiating hormone of the bursa of fabricius.

Differentiation of lymphoid precursor cells in a variety of species is induced by polypeptide hormones such as thymopoietin for T cells and bursin for B cells. In the present experiments, bursin isolated from the bursa of Fabricius of chicken was found to induce the phenotypic differentiation of mammalian and avian B precursor cells but not of T precursor cells in vitro. Similarly, bursin increased cyclic guanosine monophosphate in cells of the human B-cell line Daudi but not in cells of the human T-cell line CEM. These inducing properties of bursin are the reverse of the inducing properties of thymopoietin produced by the thymus and are appropriate to a physiological B-cell-inducing hormone. A tripeptide sequence (lysyl-histidyl-glycyl-amide) was determined for bursin and confirmed by synthesizing this proposed structure and demonstrating chemical identity of the natural and synthetic peptides. Similarity of biological action was indicated in induction assays by elevation of cyclic adenosine monophosphate and guanosine monophosphate in Daudi B cells but not in CEM T cells.

Animals↗

PubMed1986

Immunohistochemical localization of thymopoietin with an antiserum to synthetic Cys-thymopoietin28-39.

Thymopoietin-containing cells in the thymus were identified immunohistochemically using murine antiserum generated by immunization with synthetic Cys-thymopoietin28-39 (Cys-TP28-39). human thymopoietin, This antiserum, previously shown to react with both bovine and human thymopoietin, gave reactivity restricted to cortical and medullary epithelial cells of bovine and human thymus. Monoclonal antibodies with reactivity restricted to native bovine thymopoietin did not react with tissue sections of bovine thymus; most likely the epitopes recognized by monoclonal antibodies are not expressed on the inactive precursor forms of thymopoietin within thymic epithelial cells.

Animals↗

PubMed1986

Binding of thymopoietin to the acetylcholine receptor.

Thymopoietin is a polypeptide hormone of the thymus with physiological effects on the immune system and on acetylcholine-mediated transmission at the neuromuscular synapse. Elucidation of the structure and function of the nicotinic acetylcholine receptor has been facilitated by the use of the electric organs of Torpedo ray or Electrophorus eel as rich sources of the receptor and by the use of snake polypeptide toxins such as alpha-bungarotoxin as highly selective labels of the acetylcholine binding site. We now show that thymopoietin binds with high affinity (Ka approximately equal to 2.5 X 10(9) M-1) to the acetylcholine binding region of the acetylcholine receptor of Torpedo californica, as evidenced by similar and complete inhibition of the binding of radiolabeled thymopoietin or alpha-bungarotoxin by either of these polypeptides. These findings raise intriguing questions concerning the mechanisms whereby alpha-bungarotoxin and the thymopoietin affect acetylcholine receptor function, since these two polypeptides with such similar binding properties have very different functional effects.

Acetylcholine↗

PubMed1986

The influence of OKT8F treatment on allograft survival in rhesus monkeys.

The immunosuppressive effect of a monoclonal antibody specific for the cytotoxic/suppressor T cells (CD8) was investigated in rhesus monkeys. This antibody (OKT8F) removed the CD8-positive T cells from the circulation and prolonged skin allograft survival. Since most patients awaiting a kidney allograft are transfused prior to transplantation, the immunosuppressive potency of OKT8F was subsequently investigated in transfused recipients. No significant prolongation of the mean survival time was observed when OKT8F was given prophylactically. However, no early rejections were observed, while 30% of the control animals rejected their kidneys within 2 weeks. This might indicate that OKT8F prevents early rejection of a kidney allograft in transfused recipients.

Animals↗

PubMed1986

Prophylactic use of OKT3 monoclonal antibody in cadaver kidney recipients. Utilization of OKT3 as the sole immunosuppressive agent.

We describe the first clinical trial of OKT3, a monoclonal anti-T-cell antibody, for prevention of kidney transplant rejection. 13 patients receiving a first cadaveric kidney transplant were randomly assigned to conventional treatment with azathioprine and high-dose steroids (7 patients) or to treatment with daily injection of OKT3 alone (6 patients). The first OKT3 injection resulted in a dramatic decrease in T3+, T4+, and T8+ cells, while patients simultaneously experienced fever, chills, and diarrhea. These symptoms did not recur with subsequent injections. All six OKT3-treated patients had a rejection necessitating introduction of steroids 12.8 +/- 2.9 days after surgery. Rejection was related to appearance of anti-OKT3 antibodies leading to disappearance of detectable OKT3 in the serum. Modulating (T3-, T4+ or T3-, T8+) cells were observed in all patients but were functionally inactive. As no rejection was observed before day 9 posttransplant, despite the lack of additional immunosuppressive agents, we conclude that OKT3 is a powerful, well-tolerated immunosuppressive agent. However, it is highly immunogenic and anti-OKT3 antibodies lead to loss of clinical effectiveness in this protocol. The use of OKT3 alone for prevention of kidney graft rejection cannot be recommended until a method for reducing the effects of anti-OKT3 immunization is developed.

Acute Disease↗