Conversion from calcineurin inhibitors to belatacept-based immunosuppressive therapy skews terminal proliferation of non-classical monocytes and lowers lymphocyte counts.

Belatacept, a modified form of CTLA-Ig that blocks CD28-mediated co-stimulation of T cells, is an immune-suppressant that can be used as an alternative to calcineurin inhibitors (CNIs). In kidney transplant recipients, belatacept has been associated with improved renal function and reduced cardiovascular toxicity. Monocytes as well as T-lymphocytes play causal roles in the pathophysiology of atherosclerotic disease. We hypothesized that the beneficial impact of the use of belatacept over CNIs on cardiovascular risk could be partly explained by the impact of belatacept therapy on these circulating leukocytes. Hence, we phenotyped circulating leukocytes in transplanted patients with a stable renal function that were randomized between either continuation of CNI or conversion to belatacept in two international studies in which we participated. In 41 patients, we found that belatacept-treated patients consistently showed lower numbers of B-lymphocytes, T-lymphocytes as well as CD14-negative monocytes (CD14NM), especially in non-diabetic patients. Our observation that this decrease was associated to plasma concentrations of TNFα is consistent with a model where CD14NM-production of TNFα is diminished by belatacept-treatment, due to effects on the antigen-presenting cell compartment.

Activated platelets correlate with mobilization of naïve CD34(+) cells and generation of CD34(+) /KDR(+) cells in the circulation. A meta-regression analysis.

BACKGROUND: Bone marrow-derived circulating CD34(+) progenitor cells participate in remodeling and repair of the vasculature. Coexpression of the kinase-insert domain-containing receptor (KDR) has been proposed to identify the regenerative capacity. Recently, we provided evidence that the major fraction of circulating CD34(+) /KDR(+) cells is not mobilized from bone marrow, but is generated at sites of vascular injury through interaction with platelets. OBJECTIVES: To determine the relationship between platelet activation, the recruitment of naïve CD34(+) cells and the generation of CD34(+) /KDR(+) progenitor cells in a broad range of (patho)physiologic conditions, a detailed meta-regression analysis was conducted. METHODS/RESULTS: Twenty-eight conditions were found in which the numbers of CD34(+) and/or CD34(+) /KDR(+) cells and the levels of soluble P-selectin, as a marker for in vivo platelet activation, were documented. To combine heterogeneous data from 214 selected articles, results were standardized to a uniform scale by calculating standardized mean differences (SMDs) obtained from patient and control cohorts. Subsequently, a random-effects meta-regression analysis was performed on pooled SMDs. CONCLUSIONS: Our systemic survey supports a model in which activated platelets are a determinant for mobilization of CD34(+) cells from the bone marrow and the generation of CD34(+) /KDR(+) cells in the circulation.