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Concept: Transplantation medicine


Allogeneic blood or bone-marrow transplantation (alloBMT) is a potentially curative treatment for a variety of haematological malignancies and nonmalignant diseases. Historically, human leukocyte antigen (HLA)-matched siblings have been the preferred source of donor cells owing to superior outcomes compared with alloBMT using other donors. Although only approximately one-third of patients have an HLA-matched sibling, nearly all patients have HLA-haploidentical related donors. Early studies using HLA-haploidentical alloBMT resulted in unacceptably high rates of graft rejection and graft-versus-host disease (GVHD), leading to high nonrelapse mortality and consequently poor survival. Several novel approaches to HLA-haploidentical alloBMT have yielded encouraging results with high rates of successful engraftment, effective GVHD control and favourable outcomes. In fact, outcomes of several retrospective comparative studies seem similar to those seen using other allograft sources, including those of HLA-matched-sibling alloBMT. In this Review, we provide an overview of the three most-developed approaches to HLA-haploidentical alloBMT: T-cell depletion with ‘megadose’ CD34(+) cells; granulocyte colony-stimulating factor-primed allografts combined with intensive pharmacological immunosuppression, including antithymocyte globulin; and high-dose, post-transplantation cyclophosphamide. We review the preclinical and biological data supporting each approach, results from major clinical studies, and completed or ongoing clinical studies comparing these approaches with other alloBMT platforms.

Concepts: Immune system, White blood cell, Graft-versus-host disease, Leukemia, Organ transplant, Human leukocyte antigen, Hematopoietic stem cell transplantation, Transplantation medicine


Background Chronic graft-versus-host disease (GVHD) is the leading cause of later illness and death after allogeneic hematopoietic stem-cell transplantation. We hypothesized that the inclusion of antihuman T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia would result in a significant reduction in chronic GVHD 2 years after allogeneic peripheral-blood stem-cell transplantation from an HLA-identical sibling. Methods We conducted a prospective, multicenter, open-label, randomized phase 3 study of ATG as part of a conditioning regimen. A total of 168 patients were enrolled at 27 centers. Patients were randomly assigned in a 1:1 ratio to receive ATG or not receive ATG, with stratification according to center and risk of disease. Results After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was 32.2% (95% confidence interval [CI], 22.1 to 46.7) in the ATG group and 68.7% (95% CI, 58.4 to 80.7) in the non-ATG group (P<0.001). The rate of 2-year relapse-free survival was similar in the ATG group and the non-ATG group (59.4% [95% CI, 47.8 to 69.2] and 64.6% [95% CI, 50.9 to 75.3], respectively; P=0.21), as was the rate of overall survival (74.1% [95% CI, 62.7 to 82.5] and 77.9% [95% CI, 66.1 to 86.1], respectively; P=0.46). There were no significant between-group differences in the rates of relapse, infectious complications, acute GVHD, or adverse events. The rate of a composite end point of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than in the non-ATG group (36.6% vs. 16.8%, P=0.005). Conclusions The inclusion of ATG resulted in a significantly lower rate of chronic GVHD after allogeneic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic GVHD-free survival and relapse-free survival was higher with ATG. (Funded by the Neovii Biotech and the European Society for Blood and Marrow Transplantation; number, NCT00678275 .).

Concepts: Clinical trial, Graft-versus-host disease, Hematology, Organ transplant, Hematopoietic stem cell transplantation, Transplantation medicine


Graft-versus-host disease (GVHD) is a major barrier to successful allogeneic hematopoietic stem-cell transplantation (HSCT). The chemokine receptor CCR5 appears to play a role in alloreactivity. We tested whether CCR5 blockade would be safe and limit GVHD in humans.

Concepts: Immune system, Signal transduction, Graft-versus-host disease, CCR5, Chemokine, Hematopoietic stem cell transplantation, Transplantation medicine, Chemokine receptor


Immunologic graft rejection is one of the main causes of short and long-term graft failure in corneal transplantation. Steroids are the most commonly used immunosuppressive agents for postoperative management and prevention of corneal graft rejection. However, steroids delivered in eye drops are rapidly cleared from the surface of the eye, so the required frequency of dosing for corneal graft rejection management can be as high as once every 2h. Additionally, these eye drops are often prescribed for daily use for 1year or longer, which can result in poor patient compliance and steroid-related side effects. Here, we report a biodegradable nanoparticle system composed of Generally Regarded as Safe (GRAS) materials that can provide sustained release of corticosteroids to prevent corneal graft rejection following subconjunctival injection provided initially during transplant surgery. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing dexamethasone sodium phosphate (DSP) exhibited a size of 200nm, 8wt.% drug loading, and sustained drug release over 15days in vitro under sink conditions. DSP-loaded nanoparticles provided sustained ocular drug levels for at least 7days after subconjunctival administration in rats, and prevented corneal allograft rejection over the entire 9-week study when administered weekly. In contrast, control treatment groups that received weekly injections of either placebo nanoparticles, saline, or DSP in solution demonstrated corneal graft rejection accompanied by severe corneal edema, neovascularization and opacity that occurred in ≤4weeks. Local controlled release of corticosteroids may reduce the rate of corneal graft rejection, perhaps especially in the days immediately following surgery when risk of rejection is highest and when typical steroid eye drop administration requirements are particularly onerous.

Concepts: Immune system, Surgery, Immunology, Eye, Cornea, Organ transplant, Corneal transplantation, Transplantation medicine


Graft-versus-host disease (GVHD) is a lethal complication of allogeneic bone marrow transplantation (BMT). Immunosuppressive agents are currently used to control GVHD but may cause general immune suppression and limit the effectiveness of BMT. Adoptive transfer of regulatory T cells (T(regs)) can prevent GVHD in rodents, suggesting a therapeutic potential of T(regs) for GVHD in humans. However, the clinical application of T(reg)-based therapy is hampered by the low frequency of human T(regs) and the lack of a reliable model to test their therapeutic effects in vivo. Recently, we successfully generated human alloantigen-specific CD8(hi) T(regs) in a large scale from antigenically naïve precursors ex vivo using allogeneic CD40-activated B cells as stimulators. We report a human allogeneic GVHD model established in humanized mice to mimic GVHD after BMT in humans. We demonstrate that ex vivo-induced CD8(hi) T(regs) controlled GVHD in an allospecific manner by reducing alloreactive T cell proliferation as well as decreasing inflammatory cytokine and chemokine secretion within target organs through a CTLA-4-dependent mechanism in humanized mice. These CD8(hi) T(regs) induced long-term tolerance effectively without compromising general immunity and graft-versus-tumor activity. Our results support testing of human CD8(hi) T(regs) in GVHD in clinical trials.

Concepts: Immune system, Cell, Chemotherapy, Immunology, Graft-versus-host disease, Hematopoietic stem cell transplantation, Immunosuppression, Transplantation medicine


BACKGROUND: Approaches to safely induce tolerance in vascularized composite allotransplantation (VCA) with chimerism through bone marrow transplantation (BMT) are currently being pursued. However, VCA was historically performed sequentially after donor chimerism was established. Delayed VCA is not clinically applicable due to the time constraints associated with procurement from deceased donors. A more clinically relevant approach to perform both BMT and VCA simultaneously was evaluated. METHODS: Wistar Furth (RT1A) rats were treated with a short course of immunosuppressive therapy (anti-αβ-TCR monoclonal antibody, FK-506, and anti-lymphocyte serum). One day before BMT, rats were treated with varying doses of total body irradiation (TBI) followed by transplantation of heterotopic osteomyocutaneous flaps from hindlimbs of August Copenhagen Irish (RT1A) rats. RESULTS: Eighty percent of rats conditioned with 300 cGy TBI and 40% of rats receiving 400 cGy TBI accepted the VCA. Mixed chimerism was detected in peripheral blood at 1 month after VCA, but chimerism was lost in all transplant recipients by 4 months. Most peripheral donor cells originated from the BMT and not from the VCA. Acceptors of VCA were tolerant of a donor skin graft challenge and no anti-donor antibodies were detectable, suggesting a central deletional mechanism for tolerance. Regulatory T cells (Treg) from spleens of acceptors more potently suppressed lymphocyte proliferation than Treg from rejectors in the presence of donor stimulator cells. CONCLUSIONS: These studies suggest that simultaneous BMT and VCA may establish indefinite allograft survival in rats through Treg-mediated suppression and thymic deletion of alloreactive T cells.

Concepts: Immune system, White blood cell, Blood, Chemotherapy, Graft-versus-host disease, Organ transplant, Transplantation medicine, Total body irradiation


Multiple cell types contribute to the peripheral regulation of T cell alloresponses in haematopoieitc cell transplantation (HCT) and solid organ transplantation (SOT). Of these, regulatory T cells (Tregs) are the principal players and have shown the greatest success in the therapeutic control of detrimental immune responses. Investigations into the induction, location, and mechanism of suppression utilised by Tregs to control alloreactive responses are ongoing. The activation and homing characteristics of Tregs are important to their regulatory capabilities, with activation and homing occurring in the same time and space as conventional T cells. This review discusses these characteristics and recent advances in the field as we move closer to the ultimate goal of utilising Tregs as treatment for allograft rejection and graft-versus-host disease (GvHD).

Concepts: Time, Immunology, Graft-versus-host disease, Organ, T cells, Organ transplant, Hematopoietic stem cell transplantation, Transplantation medicine


Graft-versus-host disease (GVHD) remains the major obstacle for allogeneic bone marrow transplantation, in which many proinflammatory cytokines secreted by alloreactive donor T cells are involved. Role of IL-22 as a member of IL-10 family in GVHD is still disputed and the properties of IL-22-producing cells are unclear. We demonstrated here that CD4(+) T cells but not CD8(+) T cells involved in GVHD were the main cellular source of donor-derived IL-22. Th1 and Th17 cells were detected not only express classical cytokine IFN-γ or IL-17, but also contributed to IL-22 secretion in GVHD. Th22 cells characterized by the independent secretion of IL-22 were identified and occupied almost half percentage of IL-22-producing CD4(+) T cells. The frequency of IL-22-producing CD4(+) T cells showed dynamic changes with the development of GVHD. Finally, we observed that IL-22-producing CD4(+) T cells in GVHD mouse carried CD62L(-)CD44(high/low) surface markers. In conclusion, we illuminate the characteristics of donor-derived IL-22-producing CD4(+) T cells, which may have potent implication for further study of pathogenesis of GVHD.

Concepts: Immune system, Cytokine, Bone marrow, Chemotherapy, Graft-versus-host disease, Lymphatic system, Hematopoietic stem cell transplantation, Transplantation medicine


Hematopoietic macrochimerism, which is rarely seen after orthotopic liver transplantation (OLT), has been linked to the development of graft versus host disease (GvHD). We report on a patient with GvHD after OLT in whom full engraftment of donor-derived, multilineage hematopoiesis occurred, indicating that the liver contains pluripotent hematopoietic progenitor cells (HPC) capable to restore hematopoiesis in recipients. Although preventing graft rejection, standard immunosuppressive therapy may be under certain immunological conditions not sufficient to prevent GvHD. Age-, disease-, and treatment-related variables might be critical determinants for the development of an effective alloreactive T-cell response leading to the establishment of full hematopoietic chimerism.

Concepts: Immune system, Liver, Graft-versus-host disease, Organ transplant, Immunosuppression, Thymus, Transplantation medicine, Liver transplantation


BACKGROUND: Chronic rejection of vascularized composite allografts (VCA) is an emerging phenomenon that may decrease long-term allograft survival and impair allograft function. Although intimal hyperplasia has been reported in human hand transplants, chronic changes in VCAs remain poorly described. METHODS: We developed a nonhuman primate model of face transplantation to evaluate the effect of various immunosuppressive regimens on allograft survival that we have previously reported. Nineteen grafts were successfully transplanted and serially biopsied to assess for rejection. Five VCA grafts with long-term survival (>200 days) were weaned off immunosuppression. We performed additional histologic and immunohistochemical studies on previously collected samples. RESULTS: All five grafts developed features consistent with chronic rejection, including neointimal proliferation, transplant vasculopathy, vessel wall fibrosis, progressive luminal occlusion, and tertiary lymphoid follicles. Review of 186 serial allograft skin and subcutaneous tissue biopsies revealed that tertiary follicles and vascular changes developed in the absence of acute skin rejection. No relationship was found between alloantibody production and these changes. CONCLUSIONS: Recognition of these characteristics of VCA chronic rejection is important for diagnosis in clinical hand and face transplantation. Studies directed towards minimizing VCA chronic rejection responses may be required to improve long-term outcomes.

Concepts: Medicine, Pathology, Immunology, Anatomical pathology, Histology, Organ transplant, Transplantation medicine, Allotransplantation