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Biomedical subjects

G Riethmuller

Publications and source records attributed to G Riethmuller.

7 recordsLinked to original sources
PubMed1997

Cytotoxic monocytes in the blood of HIV type 1-infected subjects destroy targeted T cells in a CD95-dependent fashion.

HIV-1 infection changes the functional balance of macrophages in the body; it inhibits the development of macrophages capable of costimulating T cell responses and it favors the development of macrophages that kill T cells with which they form cellular conjugates. Cytotoxic macrophages destroy CD4 T cells, which they target through CD4-reactive immune-complexed HIV-1 envelope molecules on a large scale. They also destroy T cells that they target through presented antigen or mitogen. We show here that cytotoxic macrophages destroy their cellular targets at least partially in a CD95-dependent process in which T cells first modulate expression of most of their membrane receptors and subsequently die.

Adult↗
PubMed1994

Expression and characterization of cM-T413, a chimeric anti-CD4 antibody with in vitro immunosuppressive activity.

Anti-CD4 monoclonal antibodies (mAbs) have shown considerable promise in the treatment of rheumatoid arthritis, psoriasis, and allograft rejection and may have potential use in blocking HIV-1 infection. One such anti-CD4 mAb we have developed, chimeric M-T412 (or cM-T412), has been used in clinical trials to treat rheumatoid arthritis, generalized postular psoriasis, and other autoimmune diseases. Here we report the cloning and expression of a second chimeric anti-CD4 mAb using M-T413, a murine mAb that blocks HIV-1 infection of H9 cells. We cloned the immunoglobulin light and heavy chain variable regions of M-T413, combined them with the human kappa (light chain) or G1, G2, G3 and G4 (heavy chain) constant regions in human expression vectors, and expressed these chimeric mAbs in 653 cells. Like chimeric M-T412 IgG1, the chimeric M-T413 mAbs inhibit T-cell proliferation in the mixed lymphocyte response and thus can act to immunosuppress CD4+ T-cell response. In contrast to M-T412, however, the M-T413 chimeric mAbs have reduced activity in an antibody-dependent cell-mediated cytotoxicity (ADCC) assay using human CD4+ target and effector cells. We conclude that the chimeric M-T413 mAbs have potential utility in treating autoimmune disease and may be useful as prophylactics in preventing HIV-1 infection.

Animals↗
PubMed1993

Effects of isotype and Fc region on in vitro function of a mouse/human chimeric CD4 antibody.

Murine CD4 mAbs have shown potential for the treatment of allograft rejection and autoimmune disorders including rheumatoid arthritis. Clinical usefulness of the murine mAbs has been limited by immunogenicity and a short circulating half-life. Mouse/human chimeric antibodies have been constructed, composed of the variable region of M-T412 (a murine G2a mAb specific for the human CD4 molecule) and human G1 (cM-T412 G1) or G4 (cM-T412 G4) Fc regions. F(ab')2 and F(ab) fragments of the murine G2a and chimeric G1 mAbs were generated by enzymatic digestion. The chimeric mAbs and all fragments retained the avidity and specificity of the murine M-T412 and were evaluated in in vitro assays measuring Ig production by pokeweed mitogen (PWM)-stimulated peripheral blood mononuclear cells (PBMC), sIL-2R produced by phytohemagglutinin-stimulated PBMC, and proliferation in response to tetanus toxoid, CD3 mAb plus IL-2, and mixed lymphocyte response (MLR). When PBMC were stimulated with tetanus toxoid, 10 ng/ml of cM-T412 G1 inhibited proliferation by 90%, while neither the cM-T412 G4, M-T412 G2a, nor any mAb fragment produced > 65% inhibition, even at 1000-fold higher concentrations. A similar pattern of inhibition was observed in MLR assays. In contrast, the F(ab')2 fragment of the cM-T412 G1 was as effective as the whole antibody in inhibiting PWM-stimulated IgM synthesis and PBMC proliferation in response to stimulation by a CD3 mAb plus IL-2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

High-level expression and characterization of a mouse-human chimeric CD4 antibody with therapeutic potential.

The use of murine anti-CD4 monoclonal antibodies (MAbs) has shown considerable promise for the treatment of allograft rejection and rheumatoid arthritis. We have constructed mouse-human anti-CD4 antibodies with the goal of increasing their clinical potential by decreasing immunogenicity and improving effector functions. The chimeric antibodies were constructed by cloning the heavy and light chain variable regions of M-T412, a murine antibody raised against the human CD4 antigen, and joining them to the human G1, G4, or kappa constant regions in mammalian expression vectors. After transfection into mouse myeloma cells, stable cell lines were isolated that secrete up to 140 micrograms/ml chimeric antibody in static culture. The chimeric antibodies were equivalent to the murine antibody in their binding characteristics and relative affinities. However, the chimeric M-T412 MAbs have enhanced activity when compared to the murine G2a MAb in mediating antibody-dependent cell-mediated cytotoxicity using human CD4+ target and effector cells.

Animals↗
PubMed1988

Enhanced cytotoxicity against colon carcinoma by combinations of noncompeting monoclonal antibodies to the 17-1A antigen.

The purpose of this report was to investigate the binding specificities and ability to generate antibody dependent cell mediated cytotoxicity (ADCC) or antibody dependent complement mediated cytotoxicity of three novel monoclonal antibodies (mAbs), designated M74, M77, and M79, raised against the colorectal carcinoma antigen 17-1A. As determined by indirect radioimmunoassay, all three mAbs, as well as mAb 17-1A, bound to a similar extent to adherent cultures of the human colon carcinoma cell line, HT-29. Scatchard analysis of direct binding data for mAbs 17-1A, M74, M77, and M79 to HT-29 cells demonstrated equivalent association constants (7.54-9.77 X 10(7) liters/mol) and molecules bound per cell (2.15-2.69 X 10(5)). In contrast to mAbs M77 and M79, mAb M74 inhibited the binding of 125I-labeled mAb 17-1A to HT-29 cells. Similar to mAb 17-1A, incubation of human lymphocytes and blood monocytes with mAbs M74, M77, or M79 generated ADCC activity against HT-29 colon carcinoma cells. Various combinations of noncompeting mAbs to the 17-1A antigen (17-1A and M74; M77 and M79; M74 and either M77 or M79) but not competing mAbs (17-1A and M74; M77 and M79) resulted in a heightened level of ADCC activity. Under optimum conditions (saturation of antigenic sites with mAb), ADCC generated by the combination of noncompeting mAbs to the 17-1A antigen was additive to the activity seen with the respective mAbs alone. Under suboptimum conditions, the combination of noncompeting mAbs to the 17-1A antigen resulted in tumor cell cytotoxicity which was synergistic to the lysis obtained with the respective mAbs alone. No mAb used alone was able to generate antibody dependent complement mediated cytotoxicity against a panel of 17-1A positive colon carcinoma cells. Similarly, no antibody dependent complement mediated cytotoxicity activity was obtained with the combination of competing mAbs to the 17-1A antigen. However, HT-29 cells treated with noncompeting mAbs to the 17-1A antigen antigen were rendered susceptible to lysis by human complement. We conclude that the combination of mAbs recognizing different epitopes on the same tumor antigen could have important implications for the passive immunotherapy of cancer.

Antibodies, Monoclonal↗