Abstract
Pretransplant desensitization with rituximab has been applied to preformed donor-specific anti-human leukocyte antigen antibody (DSA)-positive recipients for elimination of preformed DSA. We investigated the impact of pretransplant desensitization with rituximab on anti-donor T cell responses in DSA-positive transplant recipients. To monitor the patients’ immune status, mixed lymphocyte reaction (MLR) assays were performed before and after desensitization with rituximab. Two weeks after rituximab administration, the stimulation index (SI) of anti-donor CD4+ T cells was significantly higher in the DSA-positive recipients than in the DSA-negative recipients. To investigate the mechanisms of anti-donor hyper responses of CD4+ T cells after B cell depletion, highly sensitized mice models were injected with anti-CD20 mAb to eliminate B cells. Consistent with clinical observations, the SI values of anti-donor CD4+ T cells were significantly increased after anti-CD20 mAb injection in the sensitized mice models. Adding B cells isolated from untreated sensitized mice to MLR significantly inhibited the enhancement of anti-donor CD4+ T cell response. The depletion of the CD5+ B cell subset, which exclusively included IL-10-positive cells, from the additive B cells abrogated such inhibitory effects. These findings demonstrate that IL-10+ CD5+ B cells suppress the excessive response of anti-donor CD4+ T cells responses in sensitized recipients.
Highlights
It has been reported that preformed donor-specific antihuman leukocyte antigen antibody (DSA) are associated with detrimental effects in transplant r ecipients[1]
We have recently shown that pretransplant desensitization with rituximab has a minimal effect on the alloreactive T cell responses by comparing ABO-blood type incompatible (ABO-I) and ABO-compatible g roups[20]
There were no significant differences in the stimulation index (SI) values for the C D4+ T cell responses between the two groups before rituximab administration (Fig. 1A,C)
Summary
It has been reported that preformed DSAs are associated with detrimental effects in transplant r ecipients[1]. Preformed class I DSA (MFI ≥ 5000) disproportionately affects patients transplanted with a high calculated model for end-stage liver disease (MELD) score and those who received lower quality organs [donor risk index (DRI) > 1.5]10. B cell depletion with the prophylactic use of rituximab has been applied in preformed DSA-positive r ecipients[14, 15]. We desensitized DSA-positive patients with rituximab and plasmapheresis, which was adopted from a protocol for ABO-blood type incompatible (ABO-I) transplant r ecipients[19]. The previous study excluded DSA-positive recipients who might have preformed donor-reactive T cells. The objective of this study was to elucidate the impact of pretransplant desensitization with rituximab on the subsequent response of T cells to donor-antigens in DSA-positive transplant recipients. A highly sensitized murine model was applied to investigate the mechanisms of the significant impacts of B cell depletion by injecting anti-CD20 monoclonal antibodies (mAbs) on anti-donor T cell responses
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