Down-Regulation of Surface CD28 under Belatacept Treatment: An Escape Mechanism for Antigen-Reactive T-Cells.

Abstract

BACKGROUND:

The co-stimulatory inhibitor of the CD28-CD80/86-pathway, belatacept, allows calcineurin-inhibitor-free immunosuppression in kidney transplantation. However, aggressive T-cell mediated allogeneic responses have been observed in belatacept-treated patients, which could be explained by effector-memory T-cells that lack membrane expression of CD28, i.e. CD28-negative (CD28NULL) T-cells. CD28-positive (CD28POS) T-cells that down regulate their surface CD28 after allogeneic stimulation could also pose a threat against the renal graft. The aim of this study was to investigate this potential escape mechanism for CD28POS T-cells under belatacept treatment.

MATERIALS & METHODS:

PBMCs, isolated T-cell memory subsets and isolated CD28POS T-cells were obtained from end-stage renal disease (ESRD) patients and co-cultured with allo-antigen in the presence of belatacept to mimic allogeneic reactions in kidney-transplant patients under belatacept treatment. As a control, IgG was used in the absence of belatacept.

RESULTS:

Despite high in vitro belatacept concentrations, a residual T-cell growth of ±30% was observed compared to the IgG control after allogeneic stimulation. Of the alloreactive T-cells, the majority expressed an effector-memory phenotype. This predominance for effector-memory T-cells within the proliferated cells was even larger when a higher dose of belatacept was added. Contrary to isolated naïve and central-memory T cells, isolated effector-memory T cells could not be inhibited by belatacept in differentiation or allogeneic IFNγ production. The proportion of CD28-positive T cells was lower within the proliferated T cell population, but was still substantial. A fair number of the isolated initially CD28POS T-cells differentiated into CD28NULL T-cells, which made them not targetable by belatacept. These induced CD28NULL T-cells were not anergic as they produced high amounts of IFNγ upon allogeneic stimulation. The majority of the proliferated isolated originally CD28POS T-cells, however, still expressed CD28 and also expressed IFNγ.

CONCLUSION:

This study provides evidence that, apart from CD28NULL T-cells, also CD28POS, mostly effector-memory T-cells can mediate allogeneic responses despite belatacept treatment.

• Authors: Gretchen N de Graav, Dennis A Hesselink, Marjolein Dieterich, Rens Kraaijeveld, Willem Weimar, Carla C Baan
• Journal: PloS one (PLoS One) Vol. 11 Issue 2 Pg. e0148604 ( 2016) ISSN: 1932-6203 [Electronic] United States
• PMID: 26919152 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD28 Antigens
• Immunosuppressive Agents
• Isoantigens
• Abatacept
• Interferon-gamma

Topics

• Abatacept (administration & dosage, pharmacology)
• Allografts
• CD28 Antigens (metabolism)
• Cell Differentiation (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Down-Regulation (drug effects)
• Humans
• Immunologic Memory (drug effects)
• Immunophenotyping
• Immunosuppressive Agents (administration & dosage, pharmacology)
• Interferon-gamma (biosynthesis)
• Isoantigens (administration & dosage)
• Kidney Failure, Chronic (immunology, therapy)
• Kidney Transplantation
• T-Lymphocyte Subsets (cytology, drug effects, immunology)