C3d plasma levels and CD21 expressing B-cells in children after ABO-incompatible heart transplantation: Alterations associated with blood group tolerance

Abstract

Background: Most children transplanted with ABO-incompatible (ABOi) hearts develop selective tolerance to donor A/B antigens, whereas anti-A/B antibodies typically re-accumulate in adults after ABOi kidney transplantation. Deficiency of essential factors linking innate and adaptive immunity in early childhood may promote development of tolerance, specifically interactions between complement split product C3d and its ligand CD21 on B cells, considering their role in augmenting "T-independent" B-cell activation.

Methods: Blood and clinical data were analyzed from children after ABOi or ABO-compatible (ABOc) heart transplantation (HTx). Plasma C3d levels were quantified by enzyme-linked immunoassay. Peripheral blood mononuclear cells (PBMC) were phenotyped by flow cytometry; expression of B-cell co-receptor components CD21 and CD81 was quantified.

Results: Fifty-five samples from pediatric HTx recipients (median age at transplant: 4.2 [range 0.03 to 20.4] months; age at sample collection: 14.6 [0.04 to 51.3] months; 53% ABOi) and 21 controls were studied. CD21-expressing B cells increased in trend with age (p = 0.079); longitudinal measures in individual patients showed a strong correlation with age. CD21 expression intensity in B-cells was not age-dependent. Plasma C3d levels did not correlate with age. Comparing ABOc vs ABOi HTx, CD21-expressing cell proportions were similar; however, serum C3d levels were significantly lower after ABOi HTx (p < 0.05).

Conclusions: In children, including HTx patients, CD21-expressing B-cells show a trend to increase with age, corresponding with improved responsiveness to polysaccharide antigens. This does not differ in patients with ABOi grafts developing tolerance to donor ABO antigens. C3d levels are not age-dependent, but reduced C3d levels after ABOi HTx suggest altered complement metabolism contributing to ABO tolerance.

Keywords: ABO; B-cell co-receptor; blood group incompatible transplant; complement; immune maturation and development; pediatric heart transplantation; tolerance.