Reduced MHC alloimmunization and partial tolerance protection with pathogen reduction of whole blood

Abstract

BACKGROUND Allogeneic blood transfusion can result in an immune response against major histocompatibility complex (MHC) antigens, potentially complicating future transfusions or transplants. We have previously shown that pathogen reduction of platelet-rich plasma (PRP) with riboflavin and UV light (UV+R) can prevent alloimmunization in mice. A similar pathogen reduction treatment is currently under development for the treatment of whole blood using riboflavin and a higher dose of UV light. We sought to determine the effectiveness of this treatment in prevention of alloimmunization. STUDY DESIGN AND METHODS BALB/c mice were transfused with untreated or UV+R treated allogeneic C57Bl/6 whole blood with or without leukoreduction. Mice were evaluated for donor specific antibodies and ex vivo splenocyte cytokine responses, as well as for changes in the frequency of regulatory T (Treg) cells. RESULTS UV+R treatment blocked cytokine priming and reduced anti-MHC alloantibody responses to transfused whole blood. Leukoreduction reduced alloantibody levels in both the untreated and UV+R groups. Mice transfused with UV+R treated whole blood had reduced alloantibody and cytokine responses when subsequently transfused with untreated blood from the same donor type. This reduction in responses was not associated with increased Treg cells. CONCLUSIONS Pathogen reduction of whole blood with UV+R significantly reduces, but does not eliminate the alloimmune response. Exposure to UV+R treated whole blood transfusion does appear to induce tolerance to alloantigens resulting in reduced anti-MHC alloantibody and cytokine responses to subsequent exposures to the same alloantigens. This tolerance does not appear to be driven by an increase in Treg cells.

The role of pathogen‐reduced platelet transfusions on HLA alloimmunization in hemato‐oncological patients

“…Universal leukoreduction significantly reduced the frequency of alloimmunization, but a residual risk remains . Recently introduced pathogen‐inactivation techniques have been hypothesized to further reduce the risk of alloimmunization . In contrast, in the recently published PREPAReS study, pathogen inactivation seemed not effective in protecting HLA Class I alloimmunization in humans .…”

“…UV‐B–illuminated WBCs failed to induce allogeneic T‐cell proliferation in vitro . Moreover, in animal models, pathogen inactivation of PCs prevented or inhibited the formation of alloantibodies after platelet transfusion, and may induce tolerance for subsequent exposures . Notwithstanding these preclinical results, pathogen inactivation–mediated reduction of alloimmunization lacks confirmation in humans.…”

The pathogen‐reduced red blood cell suspension: single centre study of clinical safety and efficacy in children with oncological and haematological diseases

“…The efficacy and clinical performance of the PRT technology which uses RF + UV to treat whole blood have been recently demonstrated in a randomized clinical studies . Moreover, this treatment abrogates the ability of contaminating WBC to present the antigen, inhibiting T‐cell proliferation, cytokine production and finally preventing transfusion‐associated graft‐versus‐host disease (ta‐GVHD) . The toxicological safety of WB treated with RF+UV has been demonstrated both in vitro as in animal studies .…”

Allogeneic major histocompatibility complex antigens are necessary and sufficient for partial tolerance induced by transfusion of pathogen reduced platelets in mice

“…While we never detected tolerance induction in vitro , it is possible that weak or more transient T‐cell interactions with treated cells could result in tolerance induction in vivo . Class I MHC is expressed on both WBCs and platelets, and while expression on platelets is much lower than on WBCs, platelet numbers are approximately two logs higher than WBC numbers in our transfused PRP . Both are sources of class I MHC alloantigen, though not necessarily equivalent.…”