Short- and long-term effects of polyclonal antibodies

Müller, Thomas; Grebe, Scott O.; Reckzeh, B; Borutta, A; Radsak, K.; Lange, H.

doi:10.1016/s0041-1345(99)00095-0

Cited by 9 publications

(14 citation statements)

References 17 publications

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“…Recovery of peripheral T-cell counts occurs gradually after the cessation of Thymoglobulin treatment. After a single dose of Thymoglobulin, T-cell counts begin to return toward baseline after about 10 days (34). Typically about 40% of patients treated with a course of Thymoglobulin (mean of 6 doses at 1.5 mg/kg/ day) recover more than 50% of the initial lymphocyte count at 3 months (4).…”

Section: Time Course Of T-cell Depletionmentioning

confidence: 99%

Mechanisms of Action of Thymoglobulin

Mueller

2007

Transplantation

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Thymoglobulin (Genzyme Transplant, Cambridge, MA) is a polyclonal rabbit anti-thymocyte globulin that consists of a mixture of different antibody specificities that interact with immune response antigens, adhesion molecules, celltrafficking molecules, and a variety of other antigens involved in heterogeneous pathways. Thymoglobulin acts as a rapid T-cell depleting agent, primarily through complement-dependent cell lysis in the blood compartment and apoptotic cell death in lymphoid tissues. Although the primary immunosuppressive effect is T-cell depletion, Thymoglobulin has also been shown to modulate cell surface markers, including a number of integrins and intercellular adhesion molecules that facilitate leukocyte adhesion to the endothelium. Treatment with Thymoglobulin has been shown to be associated with both short-and long-term changes in T-cell populations, generating altered homeostasis characterized by expansion of specific T-cell subsets that have been shown to exhibit regulatory suppressor functions. Further exploration of the mechanisms of action of Thymoglobulin will be important to guiding therapy with this widely used agent in the transplant setting, as well as in emerging therapeutic areas.

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Section: Time Course Of T-cell Depletionmentioning

confidence: 99%

Mechanisms of Action of Thymoglobulin

Mueller

2007

Transplantation

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“…The long‐term effects of rATG, 20% lower CD28 expression at 1 year, 12 and inversion of the CD4/CD8 ratio < 1 for several years 2,12,17 are associated with limited risk of CMV reactivation 17 compared to strong T–cell‐depleting serotherapies 18 . Low 3‐year cumulative incidence of EBV malignancy and non‐Hodgkin lymphoma; 0.24% (95% CI 0.2–0.58) was detected in a retrospective analysis of a large cohort of renal transplantation patients having treatments with ATG‐F 19 …”

Section: Modes Of Action Of Ratg: Short‐term T Cell Depletion Versus mentioning

confidence: 99%

“…4,5 The infusion of 2.5 mg thymoglobulin/kg bw triggers the release of Th2 cytokines; serum concentrations increase from three-to sixfold to a peak of 2,000-4,000 pg IL-6/mL and 1,000-1,500 pg TNF-␣/mL at 6 h. 6 After 24h intraoperative single high dosage infusion of 9 mg ATG-F/kg bw the mean serum concentrations increase from two-to threefold to 743 pg TNF-␣/mL and 26 pg IL-10/mL. 2,7 The levels of IL-10, IL-15, and IL-7 mRNA in peripheral blood lymphocytes are elevated from three-to fivefold at 24-48 h of ATG-F infusion. 8 Inclusion of methylprednisolone during rATG infusion counteracts the flulike syndrome of fever, chills pruritis, uticaria, joint pain, and nausea related to TNF-␣ and cytokine release.…”

Section: Modes Of Action Of Ratg: Short-term T Cell Depletion Versus mentioning

confidence: 99%

“…The CD3 counts typically decrease <150 CD3+/μL 24 h after the first rATG infusion and the counts remain at <50–100 CD3/μL with repeated infusions of 1–2 mg thymoglobulin or 3–4 mg ATG‐F/kg bw over 7–10 days. The homeostatic proliferation following rATG‐induced eukopenia typically restores the T cell counts to the range of 800–1,200 CD3 + /μL within1–2 weeks 2,12 …”

Section: Modes Of Action Of Ratg: Short‐term T Cell Depletion Versus mentioning

confidence: 99%

“…The bulk of rATG preparation is nonspecific rabbit IgG. The fraction of rATG that actually binds to cell‐surface ligands and receptors and imparts specific immunomodulatory signals is estimated at less than 0.5% of the total IgG mitogenic or superantigenic stimuli are seen at concentrations of <50 μg rATG/mL, 1,3 13 conversion of CD4 + CD25 − T cells to CD4 + CD25 + Foxp3 + T cells over a range of 7–60 μg rATG/mL 14 and apoptotic 2,4,5 and/or antiproliferative effect 1,13 over a range of 60–500 μg rATG/mL. The immunomodulatory effects of rATGs include the blockade of signals 1 and 2 of the T cell activation pathways, 12,15 inhibition of cellular adhesions, and lymphocyte migration in blood vessels during the period of ischemia reperfusion injury 16 …”

Section: Modes Of Action Of Ratg: Short‐term T Cell Depletion Versus mentioning

confidence: 99%

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Treatment of Autoimmune Disease with Rabbit Anti‐T Lymphocyte Globulin

Lytton¹,

Denton

Nutzenberger³

2007

Annals of the New York Academy of Sciences

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The rabbit anti-T lymphocyte globulins (rATGs) are immune-suppressive anti-T cell agents with beneficial effects in solid organ and hematological transplantation. The present review evaluates the potential mechanisms of rATGs and their impact on pilot and exploratory studies of diffuse cutaneous systemic sclerosis (scleroderma-SSc), inclusion body myositis (IBM), vasculitis, and type 1 diabetes mellitus (T1DM). The rATGs are associated with improvements in well-defined parameters of clinical autoimmunity: insulin usage, tissue inflammation, and systemic organ functions. Meta-analysis of a retrospective database of SSc, N = 196 and two prospective randomized pilot studies; IBM, N = 11 and T1DM, N = 17 shows a two- to ninefold increase in the relative response to treatments with intravenous infusions of rATG. The rATGs deplete T cells and are associated with increases in the percentage of CD25+ T cell subsets. This may underlie the apparent long-lasting immunomodulation associated with these agents. The future optimization of rATG adjunct therapy requires statistically powered-controlled prospective trials of rATG dose-finding and timing of administration. The potential mechanisms of rATGs:depletion of autoreactive T cells, generation CDCD25+Foxp3+ regulatory T cells (Tregs), and the acquisition of regulatory immune cell functions, need to be examined in patients prior to rATG infusion and at time intervals following rATG treatment to identify those mechanisms relevant to the improvement of their clinical outcome.

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