Antibody-mediated rejection in xenotransplantation: Can it be prevented or reversed?

Antibody-mediated rejection (AMR) is the commonest cause of failure of a pig graft after transplantation into an immunosuppressed nonhuman primate (NHP). The incidence of AMR compared to acute cellular rejection is much higher in xenotransplantation (46% vs. 7%) than in allotransplantation (3% vs. 63%) in NHPs. Although AMR in an allograft can often be reversed, to our knowledge there is no report of its successful reversal in a pig xenograft. As there is less experience in preventing or reversing AMR in models of xenotransplantation, the results of studies in patients with allografts provide more information. These include (i) depletion or neutralization of serum anti-donor antibodies, (ii) inhibition of complement activation, (iii) therapies targeting B or plasma cells, and (iv) anti-inflammatory therapy. Depletion or neutralization of anti-pig antibody, for example, by plasmapheresis, is effective in depleting antibodies, but they recover within days. IgG-degrading enzymes do not deplete IgM. Despite the expression of human complement-regulatory proteins on the pig graft, inhibition of systemic complement activation may be necessary, particularly if AMR is to be reversed. Potential therapies include (i) inhibition of complement activation (e.g., by IVIg, C1 INH, or an anti-C5 antibody), but some complement inhibitors are not effective in NHPs, for example, eculizumab. Possible B cell-targeted therapies include (i) B cell depletion, (ii) plasma cell depletion, (iii) modulation of B cell activation, and (iv) enhancing the generation of regulatory B and/or T cells. Among anti-inflammatory agents, anti-IL6R mAb and TNF blockers are increasingly being tested in xenotransplantation models, but with no definitive evidence that they reverse AMR. Increasing attention should be directed toward testing combinations of the above therapies. We suggest that treatment with a systemic complement inhibitor is likely to be most effective, possibly combined with anti-inflammatory agents (if these are not already being administered). Ultimately, it may require further genetic engineering of the organ-source pig to resolve the problem entirely, for example, knockout or knockdown of SLA, and/or expression of PD-L1, HLA E, and/or HLA-G.

Interpreting urinary iodine concentration: effects of urine dilution and collection timing.

OBJECTIVES: In population studies, iodine intake estimation relies on median urinary iodine concentration (UIC). However, interpreting UIC measurements can be challenging. METHODS: In our study, we included 772 adult participants from three groups: nationally representative gender-mixed, women of reproductive age, and pregnant women. We measured UIC and urinary creatinine (U-Cr) to calculate the iodine-to-creatinine ratio (I/Cr). U-Cr cut-off value of 0.226 g/L was used for differentiation between diluted and undiluted urine samples. After excluding samples below this cut-off, new median UIC and I/Cr ratios were calculated. We additionally evaluated the influence of urine sample collection time on UIC. RESULTS: Median UICs were 91.8 µg/L for nationally representative group, 58.3 µg/L for women of reproductive age, and 74.9 µg/L for pregnant women, while I/Cr ratios were 91.7, 102.0, and 159.2 µg/g, respectively. After implementing U-Cr cut-off and excluding all data where U-Cr was below cut-off, new median values were 93.4, 76.3, and 95.4 µg/L for UICs, and 88.6, 88.8, and 128.7 µg/g for I/Cr ratios, respectively. In women of reproductive age, median UIC was significantly lower in urine samples collected after 9:30 and after 12:00 as compared to samples collected before 9.30 (53.4, 57.8, and 97.3 µg/L, respectively). CONCLUSIONS: UIC results should be interpreted with caution, considering urine dilution and sample collection timing. U-Cr measurement should be included in population-based iodine intake studies, with corrections applied especially for pregnant women and younger adults, for whom morning is best for single-spot samples.