Institute of Hematology and Blood Transfusion, Czech Republic
Title: Hematopoietic stem cell-based therapy for HIV disease: Prostaglandinmodulated transplantation
Biography: Josef Bodor
At present, the general consensus is that ‘true’ self-renewing human hematopoietic stem cells (HSCs) are found within the CD34+ populationrnand that engraft ment of a suitably conditioned host with a suffi cient number of such cells will result in long-term multilineage hematopoiesis.rnUmbilical Cord Blood (UCB) cells are a valuable source of HSCs for use in allogeneic transplantation. Key advantages are easy availability andrnless stringent requirements for HLA matching. However, UCB cells contain an inherently limited HSC count associated with delayed time ofrnengraft ment, high graft failure rates and early mortality. PGE2 derivative (16, 16 dimethylprostaglandin E2; dmPGE2) was recently identifi edrnto be a critical regulator of HSC homeostasis (1). Recent data have shown that brief ex vivo modulation with dmPGE2 could improve patientrnoutcomes by increasing the ‘eff ective dose’ of HSCs with preferential long-term engraft ment of the dmPGE2 treated HSCs in allogeneicrntransplantation. Moreover, it was demonstrated that conventional CD4+ T cells (Tcons) could be developed in vitro into CD4+CD25+Foxp3+rninducible regulatory T cells (iTregs) with an equivalent suppressive potential as naturally occuring regulatory T cells (nTregs) by continuousrnpolyclonal activation with anti-CD3/CD28 mAbs (2). During the diff erentiation process, the iTregs express cyclooxygenase 2 (COX-2) andrnproduce PGE2. Interestingly, neither resting nor activated nTregs express COX-2. Th e PGE2 production from iTregs can be fully suppressed byrnthe COX inhibitor indomethacin. Th ese data indicate that PGE2 plays an important role in diff erentiation of HSCs thus releasing stringencyrnrequired for HLAmatching donors with potential recipients as well as with potential role in dominant suppressive eff ects of iTregs expressingrnCOX-2 with acquired ability to produce copious amounts of PGE2 responsible for delivery of suppressive function through elevated levels ofrncAMP (3). Prostaglandin E2 (PGE2)-mediated mechanisms, which have potential to downregulate CCR5 expression in umbilical cord bloodrn(UCB) cells heterozygous for CCR5Δ32 mutation (CCR5wt/Δ32), could reduce or eliminate surface expression of CCR5 (CCR5 null cells)rnand thus facilitate allogeneic transplantation, UCB cell-engraft ment, and preferential cord chimerism in parallel with CCR5 downregulation.rnKey advantages of this process are higher frequency of heterozygous CCR5wt/Δ32 donors, less stringent requirements for HLA matching,rnand better engraft ment of the cells resistant to HIV. To eliminate the need for indefi nite treatment, our ultimate goal is to create a functionalrnHIVresistant immune system through the use of modifi ed HSCs with emphasis on post-transplant amelioration of GvHD enabled viarnpotentiation of regulatory T cell (Treg) cell-mediated suppression.