Alterations in the immune phenotype of thymectomized children and the development of atopic disorders after heart transplantation.

BACKGROUND: Atopic disorders are more common in children after heart transplant (HTx). We hypothesized that HTx at an early age and thymus excision (TE) affect development of T and B cells, especially regulatory T cells (Tregs), which help maintain tolerance. METHODS: In this single-center study including 24 patients transplanted between 2013 and 2018, we investigated lymphocyte patterns in relation to these factors using flow cytometry. Clinical data were collected from standardized questionnaires and medical charts. Patients were stratified into TE and non-TE groups as well as patients with and without post-transplant atopy development/worsening. RESULTS: 64% of TE patients experienced new or worsening asthma/eczema post-transplant compared to 20% of non-TE patients. TE patients had higher total Treg proportions (CD4+CD25+CD127lo) than non-TE patients (p = .043), but borderline significantly lower naïve Tregs (CD45RA+CD27-) (p = .057). Memory CD4+ T cells were higher in TE patients in trend (p = .084). Total Tregs did not differ between atopic/nonatopic groups, although naïve Tregs were significantly lower in atopic patients (p = .028). Memory CD4+ T cells were higher in atopic patients in trend (p = .082). IgM+IgD+ B cells were higher in nonatopic patients in trend (p = .064). CONCLUSIONS: New/worsening atopy is more common in thymectomized HTx children and is associated with alterations in T-cell profiles. Avoiding TE may prevent these alterations and reduce incidence of atopy post-HTx.

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

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.

ABO-incompatible heart transplantation in early childhood: an international multicenter study of clinical experiences and limits.

BACKGROUND: Intentional blood group (BG)-incompatible (ABOi) heart transplantation in childhood is emerging in many centers. Safety limits remain undetermined. In this multicenter study we have compiled experience on clinical and immunologic boundaries. METHODS: Data from six centers in Europe and North America on ABOi transplantation were collected in a standardized survey. RESULTS: Fifty-eight ABOi transplants were performed in 57 patients. Median age at transplant was 6.8 months (0.03 to 90 months); post-transplant follow-up was 37.7 months (0.46 to 117 months), accumulating 188 patient-years. Forty-seven percent of the patients received pretransplant mechanical circulatory support. Donors were either blood group A (n = 25), B (n = 18) or AB (n = 15). The median peak antibody titer to the donor BG pretransplant was 1:8 (0 to 1:64) for anti-A and 1:4 (0 to 1:32) for anti-B. Titers against the donor BG were lower post- than pretransplant in B recipients (p = 0.02), whereas third-party antibodies in BG O recipients developed normally post-transplant. Induction immunosuppression included anti-thymocyte globulin (61%), basiliximab (32%) or none (7%). All patients received calcineurin inhibitors, including 62% with mycophenolate mofetil, 10% with azathioprine, 2% with everolimus and 24% with steroids. There were 4 episodes of cellular rejection (Grade≥2R) and 7 antibody-mediated rejections. Five patients underwent antibody removal post-transplant. One patient developed severe graft vasculopathy. Freedom from death or retransplantation was 100%/96%/69% at 1/5/10 years. No graft loss was attributed to BG antibodies. CONCLUSIONS: Successful ABOi heart transplantation can be performed at an older age and with higher isohemagglutinin titers than initially assumed and using similar immunosuppressive regimens as for ABO-compatible transplants. Rejection and graft vasculopathy are rare. Persistently low titers of antibodies to the donor BG post-transplant suggest elements of tolerance and/or accommodation.