*Purpose: Acute Graft-versus-Host Disease (GvHD) is a rare but frequently lethal complication after solid organ transplantation (SOT). In intestinal transplant recipients, anti-HLA Donor-Specific Antibody (DSA) were found to hasten the clearance of donor lymphoid cell in the blood and the allograft. We thus hypothesized that transfusion of plasma with high levels of antibodies targeting at least one donor mismatched HLA antigen, could control GVHD in such setting.

*Methods: We faced a therapeutic dead-end in an immune-deficient child with severe steroid-resistant GvHD after a kidney transplantation. Despite high-dose steroids, cholestatic hyperbilirubinemia worsened and a profound marrow aplasia occurred. An urgent nationwide search among 3800 registered blood donors with known anti-HLA immunization identified 5 potential donors, 3 of whom underwent plasma donation. We aimed at achieving an in vivo DSA mean fluorescence intensity (MFI) comprised between 2,500 and 5,000 through a 4-fold dilution of the collected plasma. The DSA was measured at 4439 and 3907 MFI units in the 4-fold diluted plasmas #1 and #2.

*Results: The patient, with an estimated plasma volume of 600 mL, received 200 mL of plasma #1 and plasma#2, three days apart. Rapid DSA adsorption on donor cells was supported by rapid drop in MFI post-infusion. Plasma transfusions were remarkably well tolerated, with no discernable kidney allograft toxicity. The patient had been experiencing severe neutropenia (<0.5 G/L) and major hyperbilirubinemia (>10 mg/dL) for 15 and 6 days, respectively. The day following the infusion, white cell count rose sharply, meanwhile the bilirubin dropped. At day6 post-infusion, the neutrophil count peaked at 4.4 G/L, while total bilirubin decreased to 3.8 mg/dL. Within a week, the general status dramatically improved. Diarrhea completely and durably resolved, and the child gained 2 kg over 5 weeks. Steroids doses were progressively tapered down and stopped on POD311. Before the first plasma transfusion, roughly 99% of the circulating CD3+ T cells were donor-derived. An unusual flow cytometry staining pattern was noticed in a subset of donor T cells that co-expressed the recipient-specific HLA-A2 molecule, yet at a lower level compared to recipient T cells. Imaging of these cells unveiled that this pattern resulted from recipient-derived extracellular microvesicles bound to donor T cells. Strikingly, this T cell subset sharply decreased as early as 3 days after the first infusion and was barely sizeable thereafter.

*Conclusions: An innovative immunotherapy strategy, coined donor-targeted serotherapy, based on the transfer of anti-HLA DSA, can successfully rescue a refractory SOT-associated GvHD.

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