Treatment with depleting CD4 monoclonal antibody results in a preferential loss of circulating naive T cells but does not affect IFN-gamma secreting TH1 cells in humans.

Rep, M.H.G.; Oosten, Bob W. van; Roos, M. T. L.; Adèr, H.J.; Polman, Chris H.; Lier, René A. W. van

doi:10.1172/jci119396

Cited by 88 publications

(51 citation statements)

References 58 publications

(47 reference statements)

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“…This could be explained by differences in pathogenesis, but also by differences in treatment. It has been shown previously that Th1-like cells are relatively spared after treatment with anti-CD4-depleting antibody (49,50). In contrast, alefacept treatment specifically reduces the memory cell population.…”

Section: Discussionmentioning

confidence: 87%

Alefacept treatment in psoriatic arthritis: Reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis

Kraan

Kuijk

Dinant

et al. 2002

Arthritis & Rheumatism

135

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Objective. To investigate whether alefacept (a fully human lymphocyte function-associated antigen 3 [LFA-3]/IgG1 fusion protein that blocks the LFA-3/CD2 interaction) is able to reduce the signs and symptoms of joint inflammation in patients with active psoriatic arthritis (PsA).Methods. Eleven patients with active PsA were treated with alefacept for 12 weeks in an open-label and explorative study. Clinical joint assessment and laboratory assessments were performed at baseline and after 4, 9, 12, and 16 weeks of treatment. Serial synovial tissue (ST) biopsy specimens from an inflamed index joint (knee, ankle, wrist, or metacarpophalangeal joint) were obtained by arthroscopy at baseline and after 4 and 12 weeks of treatment.Results. At the completion of treatment, 6 of 11 patients (55%) fulfilled the Disease Activity Score (DAS) response criteria. Nine patients (82%) fulfilled the DAS response criteria at any point during the study. There was a statistically significant reduction in CD4؉ lymphocytes (P < 0.05), CD8؉ lymphocytes (P ‫؍‬ 0.05), and CD68؉ macrophages (P < 0.02) in the ST after 12 weeks of treatment compared with baseline. The ST and peripheral blood of those patients fulfilling the DAS response criteria contained more CD45RO؉ cells at baseline and displayed a significant reduction in these cells compared with nonresponding patients.Conclusion. The changes in ST, together with the improvement in clinical joint scores, after treatment with alefacept support the hypothesis that T cell activation plays an important role in this chronic inflammatory disease. Furthermore, since alefacept, a T cellspecific agent, led to decreased macrophage infiltration, the data indicate that T cells are highly involved in synovial inflammation in PsA.

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Section: Discussionmentioning

confidence: 87%

Alefacept treatment in psoriatic arthritis: Reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis

Kraan

Kuijk

Dinant

et al. 2002

Arthritis & Rheumatism

135

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“…Several studies have tried to explain why CD4 depletion had no therapeutic effect for autoimmune disorders. In multiple clinical trials, aCD4 preferentially depleted na€ ve CD4 cells and tended to preserve memory CD4 cells (17,45,46). One study estimated that unprimed CD4 cells were 3 times more sensitive …”

Section: Discussionmentioning

confidence: 99%

Foxp3+ T Cells Inhibit Antitumor Immune Memory Modulated by mTOR Inhibition

et al. 2014

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Inhibition of mTOR signaling enhances antitumor memory lymphocytes. However, pharmacologic mTOR inhibition also enhances regulatory T-cell (Treg) activity. To counter this effect, Treg control was added to mTOR inhibition in preclinical models. Tregs were controlled with CD4-depleting antibodies because CD4 depletion has high translational potential and already has a well-established safety profile in patients. The antitumor activity of the combination therapy was CD8 dependent and controlled growth of syngeneic tumors even when an adoptive immunotherapy was not used. Lymphocytes resulting from the combination therapy could be transferred into na€ ve mice to inhibit aggressive growth of lung metastases. The combination therapy enhanced CD8 memory formation as determined by memory markers and functional studies of immune recall. Removal of FoxP3-expressing T lymphocytes was the mechanism underlying immunologic memory formation following CD4 depletion. This was confirmed using transgenic DEREG (depletion of regulatory T cells) mice to specifically remove Foxp3 þ T cells. It was further confirmed with reciprocal studies where stimulation of immunologic memory because of CD4 depletion was completely neutralized by adoptively transferring tumor-specific Foxp3 þ T cells. Also contributing to tumor control, Tregs that eventually recovered following CD4 depletion were less immunosuppressive. These results provide a rationale for further study of mTOR inhibition and CD4 depletion in patients. Cancer Res; 74(8); 2217-28. Ó2014 AACR.

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“…Common side-effects associated with depletion with anti-T-cell Abs include lymphopenia, lasting up to 5 years in some cases. Pharmacodynamic studies imply that the inefficient control of RA is due to the preferential killing of naïve T cells, rather than pathogenic synovial T cells or poor delivery of antibodies to the synovium (40,41). These observations suggest that therapies specifically targeting pathogenic T cells might lead to clinical improvements in RA.…”

Section: Discussionmentioning

confidence: 99%

Rosmarinic Acid Induces Apoptosis of Activated T Cells from Rheumatoid Arthritis Patients via Mitochondrial Pathway

Hur¹,

Suh

Kim³

et al. 2006

J Clin Immunol

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Treatment with depleting CD4 monoclonal antibody results in a preferential loss of circulating naive T cells but does not affect IFN-gamma secreting TH1 cells in humans.

Abstract: CD4

Cited by 88 publications

References 58 publications

Alefacept treatment in psoriatic arthritis: Reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis

Alefacept treatment in psoriatic arthritis: Reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis

Foxp3+ T Cells Inhibit Antitumor Immune Memory Modulated by mTOR Inhibition

Rosmarinic Acid Induces Apoptosis of Activated T Cells from Rheumatoid Arthritis Patients via Mitochondrial Pathway

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