Reprogramming the Immune System for Peripheral Tolerance with CD4 and CD8 Monoclonal Antibodies

Cobbold, Stephen; Qin, Shixin; Leong, Louise; Martin, Graham D.; Waldmann, Herman

doi:10.1111/j.1600-065x.1992.tb01423.x

Cited by 132 publications

(69 citation statements)

References 77 publications

(62 reference statements)

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“…Whilst the full significance of this is uncertain, there is an infection risk [1,16,28] which detracts from the otherwise impressive clinical results achieved in a variety of settings [12][13][14]. Animal studies suggest that a combination of lymphocyte depletion followed by blockade may be required to control a large autoreactive lymphocyte pool [17]. Furthermore, B cells, T cells and monocytes are all involved in the immunopathogenesis of RA, and all express CD52.…”

Section: Discussionmentioning

confidence: 99%

“…This characteristic has been exploited in vivo in the therapy of subsets of patients with lymphoma [11] and autoimmunity [12][13][14] using CAMPATH-1H, a CD52 MoAb of human IgG1 isotype. Although a potentially useful MoAb, the degree and duration of lymphopenia produced by CAMPATH-1H was unexpected [15,16], and almost certainly unnecessary for therapy of autoimmune disease, where non-depleting MoAbs are at least as efficacious [17]. A further unwanted effect was the 'first-dose' reaction comprising fever, chills, nausea and headache.…”

Section: Introductionmentioning

confidence: 99%

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A therapeutic human IgG4 monoclonal antibody that depletes target cells in humans

Isaacs

Wing

Greenwood³

et al. 1996

Clinical and Experimental Immunology

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It is traditionally held that human IgG4 MoAbs should not deplete target cells in vivo, as this isotype is inactive in a number of in vitro assays that measure effector function. We have previously challenged this dogma, and the current study was designed to investigate the in vivo biological effects in humans of a MoAb of human IgG4 isotype. Nine patients with refractory rheumatoid arthritis (RA) fulfilling ARA criteria, and one with ankylosing spondylitis (AS) received a human IgG4 Campath‐1 MoAb (with specificity against the pan‐lymphocyte antigen CD52) as part of a two‐stage therapeutic protocol. In stage 1, patients received a single dose of this MoAb. Stage 2, starting 48 h later, comprised a 5‐day course of a human IgG1 Campath‐1 MoAb with identical V‐region (CAMPATH‐1H), as previously used in the management of RA patients. The intervening 48 h provided a window of opportunity to monitor the biological effects of the IgG4 MoAb for comparison with the IgG1. The two MoAbs were also compared for in vitro biological activity. IgG4 depleted peripheral blood lymphocytes (PBL), albeit less efficiently than IgG1. It produced a first‐dose reaction of similar intensity, although associated circulating tumour necrosis factor‐alpha (TNF‐α) levels were lower. TNF‐α release from whole blood in vitro was also greater with the IgG1 MoAb. The study design did not permit conclusions to be drawn regarding therapeutic efficacy of the IgG4 MoAb. In summary, a human IgG4 Campath‐1 MoAb depletes target cells in vivo. Importantly, this study demonstrates for the first time in humans that in vitro assays may not predict the in vivo effector function of therapeutic MoAbs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A therapeutic human IgG4 monoclonal antibody that depletes target cells in humans

Isaacs

Wing

Greenwood³

et al. 1996

Clinical and Experimental Immunology

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“…Allotolerance in rodents has been achieved both in mice [43] and rats [44][45] (Table 3). At the moment, there are difficulties in transferring these allograft results to higher animals, but the possibility is very tempting and one can imagine a great future for this form of immunosuppression because the transplanted animals are specifically tolerant to the transplant and functioning normally in all other respects.…”

Section: Figmentioning

confidence: 99%

Xenotransplantation

Kemp

1996

Journal of Internal Medicine

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“…CD4 MAb have been shown to be effective in experimental transplantation studies (19) and in the treatment of autoimmune disease in animal models (3,4). It has been suggested that temporary blockade of the CD4 receptor could lead to a state of tolerance (19).…”

Section: Van Der Lubbe Et Almentioning

confidence: 99%

“…It has been suggested that temporary blockade of the CD4 receptor could lead to a state of tolerance (19). CD4 MAb have been used for the treatment of advanced RA in a limited number of patients.…”

Section: Van Der Lubbe Et Almentioning

confidence: 99%

A randomized, double‐blind, placebo‐controlled study of cd4 monoclonal antibody therapy in early rheumatoid arthritis

Lubbe¹,

Dijkmans²,

Markusse³

et al. 1995

Arthritis & Rheumatism

144

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Objective. To assess the efficacy of the CD4 monoclonal antibody (MAb) cM-T412 in the treatment of early rheumatoid arthritis (RA).Methods. Sixty patients were enrolled in a 6-week randomized, double-blind, placebo-controlled study investigating multiple dose regimens of cM-T412. Thirty patients subsequently were enrolled in a 9-month randomized, double-blind, placebo-controlled study investigating monthly single-dose adminiitrations of cM-T412.Results. Analysis of clinical parameters revealed no changes in arthritis activity in the groups that received CD4 MAb or the placebo group, and no difference between the groups, in either in the first or the second part of the study. The number of circulating CD4+ cells decreased substantially in the patients treated with CD4 MAb. Conclusion. CD4 MAb treatment of patients with early RA induced no therapeutic effect.Present understanding of the pathogenesis of rheumatoid arthritis (RA) is incomplete. However, accumulating evidence has indicated that the T lymphocyte orchestrates an autoimmune process (I). Therefore, surface antigens of T cells were suggested as possible targets for a specific immunotherapy .Monoclonal antibodies (MAb) against the CD4 molecule were shown to modulate the function of CD4+ T cells (2). Following the successful use of CD4 MAb in

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Reprogramming the Immune System for Peripheral Tolerance with CD4 and CD8 Monoclonal Antibodies

Cited by 132 publications

References 77 publications

A therapeutic human IgG4 monoclonal antibody that depletes target cells in humans

A therapeutic human IgG4 monoclonal antibody that depletes target cells in humans

Xenotransplantation

A randomized, double‐blind, placebo‐controlled study of cd4 monoclonal antibody therapy in early rheumatoid arthritis

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