From Antilymphocyte Serum to Therapeutic Monoclonal Antibodies: First Experiences with a Chimeric CD4 Antibody in the Treatment of Autoimmune Disease

Riethmuuller, Gert; Rieber, Ernst Peter; Kiefersauer, Stefan; Prinz, J.; Lubbe, P. A. Van Der; Meiser, Bruno; Breedveld, F. C.; Eisenburg, J; Kruuger, Klaus; Deusch, K; Sanders, Martin; Reiter, Christian

doi:10.1111/j.1600-065x.1992.tb01420.x

Cited by 58 publications

(17 citation statements)

References 47 publications

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“…In vivo injection of anti-CD4, a therapeutic modality in autoimmune diseases (35,36), results in rapid, Fas-dependent apoptosis of CD4+ T cells in the circulation (5). When anti-CD3 antibody is coinjected, cells do not undergo apoptotic death (37).…”

Section: Methodsmentioning

confidence: 99%

Fas (CD95) expression and death-mediating function are induced by CD4 cross-linking on CD4+ T cells.

Desbarats

Freed

Campbell

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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The CD4 receptor contributes to T-cell activation by coligating major histocompatibility complex class II on antigen presenting cells with the T-cell receptor (TCR)/ CD3 complex, and triggering a cascade of signaling events including tyrosine phosphorylation of intracellular proteins. The CD4 coreceptor and the T-cell receptor(TCR)/CD3 complex on T cells bind peptide-major histocompatibility complex class II complexes on antigen presenting cells during antigen specific immune responses (1). CD4 contributes to T-cell activation by signaling via its associated src-family tyrosine kinase, p56lck (lck), which phosphorylates the CD3 'y, s, and ; chains (2). CD4 coengagement with the TCR facilitates T-cell activation. In contrast, CD4 cross-linking prior to activation via the TCR results in apoptotic cell death (3). CD4 cross-linking by HIV glycoprotein (gp) 120 also results in apoptosis (4). Furthermore, in vivo CD4 ligation by injection of anti-CD4 antibodies triggered loss of surface CD4 expression, and DNA fragmentation and death (5). In vivo CD4-induced apoptosis appeared to be Fas (CD95)-dependent, since it did not occur in MRL-lpr/lpr mice, which have a mutation in the Fas gene resulting in a nonfunctional protein.Fas, a member of the tumor necrosis factor receptor family, is a mediator of cell death (6). Fas-Fas ligand (FasL) interactions mediate activation-induced cell death, the apoptotic death which follows TCR/CD3-induced T-cell activation (7-9). In vivo, Fas/FasL are thought to be responsible for controlling clone size after expansion in responses to peptide antigens and superantigens, and thus are critical in the regulation of immune homeostasis (10, 11). Fas knockout mice and mice with natural mutations in the Fas or FasL genes, lpr (lymphoproliferative) and gld (generalized lymphoproliferative defect), respectively, develop massive lymphadenopathy that becomes worse with age (12)(13)(14).In this report we demonstrate that CD4 cross-linking induces a small but rapid increase in cell surface Fas expression on isolated CD4+ T lymphocytes. CD4 crosslinking also results in Fas-dependent cell death in normal and gld, but nor lpr, strains of mice. Finally, we show that CD4 cross-linking triggers a subset of CD4+ cells to become sensitive to Fasinduced cell death, by a mechanism separate from control of Fas surface expression. MATERIALS AND METHODSMice. Female mice 6-10 weeks of age were obtained from the The Jackson Laboratories. Mice of the inbred strains C3H, C3H-lpr/lpr, and C3H-gld/gld were used. CD4+ Cell Isolation. Single cell suspensions were prepared from murine spleens and depleted of erythrocytes with Gey's solution. CD4+ cell isolation was accomplished by negative selection on commercial CD4 isolation columns (Biotex Laboratories, Edmonton, Canada). In normal mice, yields were 90% or more CD4+ cells as determined by flow cytometry. In lpr andgld mutant mice, a larger percentage of CD4-cells were present due to the accumulation of CD3+4-8-cells (15), which could not be removed by the negativ...

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Section: Methodsmentioning

confidence: 99%

Fas (CD95) expression and death-mediating function are induced by CD4 cross-linking on CD4+ T cells.

Desbarats

Freed

Campbell

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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“…The rationale for using CAMPATH-1H in the therapy of rheumatoid arthritis is based on favourable results with other anti-lymphocyte therapies, such as total lymphoid irradiation, 10 thoracic duct drainage, 11 and cyclosporin A. 12 The disease association with HLA, 13 and the observations that a number of mAbs that target T cells 14,15 have shown benefit in RA, albeit of limited duration, provide strong evidence that T cells play a role in the pathogenesis of the disease. Early results with the use of CAMPATH-1H to treat RA patients were promising, as 7/8 patients treated with a cumulative dose of 60 mg over 10 days showed initial clinical improvement, although the duration of response varied from 1-6 months.…”

Section: Introductionmentioning

confidence: 99%

Repopulation of blood lymphocyte sub‐populations in rheumatoid arthritis patients treated with the depleting humanized monoclonal antibody, CAMPATH‐1H

et al. 1996

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SUMMARYPatients with severe rheumatoid arthritis who had failed treatment with conventional therapies were treated with a course of five or 10 daily intravenous infusions of CAMPATH-1H, a humanized antibody against the CD52 antigen, resulting in profound depletion of peripheral blood mononuclear cells. During the subsequent 18 months, lymphocytes were analysed for sub-populations by fluorescenceactivated cell sorter (FACS) and for proliferation in response to polyclonal T-cell stimulation with anti-CD3 or staphylococcal enterotoxin B (SEB). Treatment resulted in almost complete depletion of lymphocytes from the blood followed by gradual repopulation. CD16 natural killer (NK) cells and CD14 monocytes returned to pretreatment levels within 1-2 months. CD19 B cells returned to within 50% of pre-treatment levels by day 66 and to within normal range by day 150, whereas CD8T cells recovered to 50% of pretreatment levels by day 66, but did not show any further increase during the rest of the study period. The most profound effects were on the CD4T lymphocyte sub-population, as the mean CD4 count did not increase above 20% of pre-treatment level at any time during the study period (550 days), at all the doses tested. The T cells which initially repopulated the blood 1-2 months after treatment, nearly all expressed the activation markers human leucocyte antigen (HLA)-DR and CD45RO, although the percentage of T cells expressing these molecules gradually declined to normal levels over time. Proliferative responses to polyclonal T-cell stimulation (anti-CD3 and SEB) were also significantly reduced in the first few months after treatment, but recovered to pre-treatment levels by day 250. The relationship between these observations and the clinical response is discussed.

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“…Furthermore, we observed substantial lymphocyte apoptotic activity in the blood of mice within 6 h of anti-CD4 treatment; more than one-third of the lymphocytes exhibited DNA degradation.These findings add new facets to the complex immunoregulatory capacity of coreceptors. Engaged together with the Tcell antigen receptor (TCR) CD4 enhances immune reactions [15, 161 whereas when ligated independently of the TCR CD4 inhibits the activation of Tcells [3, 161, initiates their deletion in vitro [17,18] or causes their deletion in vivo [19] through apoptosis (see accompanying report). HIV, through its appropriately cross-linked human CD4 binding [20] envelope molecule, gp120, can utilize CD4 signaling.…”

Section: Discussionmentioning

confidence: 99%

Deletion of T lymphocytes in human CD4 transgenic mice induced by HIV‐gp120 and gp120‐specific antibodies from AIDS patients

et al. 1994

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CD4, a T cell receptor for major histocompatibility complex class II antigen, is a key regulator of immunological reactivities. When engaged together with the T cell antigen receptor, CD4 enhances immune reactions, whereas when ligated independently of the antigen receptor CD4 inhibits the activation of T cells or initiates their deletion. CD4 serves also as a receptor for the human immunodeficiency virus (HIV), which binds the receptor with high avidity through its envelope molecule, gp120. Studies in tissue culture have shown that its affinity to CD4 gives the virus opportunities to utilize CD4-mediated signaling and to manipulate immunocytes. We show here in human CD4 transgenic mice that appropriately cross-linked HIV envelope protein causes massive deletion of HIV-reactive T cells in vivo.

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From Antilymphocyte Serum to Therapeutic Monoclonal Antibodies: First Experiences with a Chimeric CD4 Antibody in the Treatment of Autoimmune Disease

Cited by 58 publications

References 47 publications

Fas (CD95) expression and death-mediating function are induced by CD4 cross-linking on CD4+ T cells.

Fas (CD95) expression and death-mediating function are induced by CD4 cross-linking on CD4+ T cells.

Repopulation of blood lymphocyte sub‐populations in rheumatoid arthritis patients treated with the depleting humanized monoclonal antibody, CAMPATH‐1H

Deletion of T lymphocytes in human CD4 transgenic mice induced by HIV‐gp120 and gp120‐specific antibodies from AIDS patients

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