Lynne M. Ball

Mesenchymal stromal cells (MSCs) can be isolated from several human tissues and expanded for clinical use. MSCs are identified by phenotypic and functional characteristics, and are poor Ag-presenting cells not expressing MHC class II or co-stimulatory molecules. MSCs have potent immune-modulatory effects and in vitro induce a more anti-inflammatory or tolerant phenotype. Clinical studies have exploited both the immune-modulatory properties of MSCs as well as their hematopoietic supportive role. MSCs have been safely administered for the treatment of severe steroid refractory GVHD. A phase I/II multicenter study included 25 children in whom 80% responded to either one or two infusions of MSCs derived mainly from third party donors. Twenty children have undergone co-transplantation of haploidentical MSCs with PBSC in a phase I/II study, which has overcome the problems of graft failure in HLA-disparate grafts. Similarly, co-transplantation of MSCs and cord blood stem cells is under investigation. MSCs may have important future potential for the treatment of pediatric autoimmune disease as well as inborn errors such as osteogenesis imperfecta. Currently, much needed randomized studies under the auspices of the EBMT are ongoing to determine the optimal use of these exciting new modalities of treatment.

Allogeneic hematopoietic SCT (HSCT) is an established treatment for some children with life-threatening hematological disease, immune deficiencies and inborn errors of metabolism. Despite advances in prevention and post transplant immuno-suppressive strategies, acute GvHD (aGvHD) remains a major cause of morbidity and mortality in children undergoing SCT. Although reported incidence rates differ, it has been estimated that, depending upon the patient and donor cohort studied, 20–50% of all transplanted patients will experience grade 2 or more aGvHD despite immuno-suppressive prophylaxis. aGvHD occurs when transplanted donor T lymphocytes recognize antigenic disparities between the host and recipient. Pathways other than direct T-cell-mediated cytotoxicity have been shown to be important in the pathogenesis. Inflammatory cytokine release has been implicated as the primary mediator of aGvHD and activation of T cells is one step in the complex process. Deregulated cytokine release by cells other than T cells leads to tissue damage associated with aGvHD. GvHD is a factor that compromises the overall success rate of allogeneic HSCT and remains a challenge, which, in turn, requires an understanding of the pathophysiology, clinical presentation and management of this complication. The authors concentrate on the most recent knowledge of the pathogenesis as well as the classification of aGvHD.

Haploidentical hematopoietic stem-cell transplantation (HSCT) is associated with an increased risk of graft failure. Adult bone marrow–derived mesenchymal stromal cells (MSCs) have been shown to support in vivo normal hematopoiesis and to display potent immune suppressive effects. We cotransplanted donor MSCs in 14 children undergoing transplantation of HLA-disparate CD34+ cells from a relative. While we observed a graft failure rate of 15% in 47 historic controls, all patients given MSCs showed sustained hematopoietic engraftment without any adverse reaction. In particular, children given MSCs did not experience more infections compared with controls. These data suggest that MSCs, possibly thanks to their potent immunosuppressive effect on alloreactive host T lymphocytes escaping the preparative regimen, reduce the risk of graft failure in haploidentical HSC transplant recipients.

Background Although delayed red cell engraftment and/or hemolysis have been thoroughly documented in association with ABO incompatibility between donor and recipient in patients undergoing hematopoietic stem cell transplantation (HSCT), there are no studies defining the general, long term clinical outcome in a large group of pediatric patients. Methods We undertook a retrospective single center analysis of children undergoing pediatric allogeneic stem cell transplantation to determine the influence of ABO donor/recipient incompatibility. Outcome was analyzed according to donor type and included survival, graft versus host disease (GvHD), relapse, days of infection, antibiotic use, transfusion requirement and duration of hospital stay. Results Two hundred and sixteen children (136 males; 80 females, aged 0–19) transplanted between January 1992 and December 2003 were included in the study. Indications for transplantation were hematological malignancies (n = 179) and aplastic conditions (n = 37). ABO compatibility was documented in 121 donor/recipient pairs. ABO incompatibility was documented in 95 donor/recipient pairs with 40 major, 40 minor and 15 bi-directional incompatible pairs. ABO incompatibility did not influence survival rate (P = 0.3762), the incidence of GvHD (P = 0.253) or rate of relapse (P = 0.930). Recovery of leucocytes was influenced by ABO incompatibility (P = 0.0493), but the rate of infection, transfusion requirements and duration of hospital stay are not. Conclusion In the pediatric setting, ABO major and/or minor mismatch between donor and recipient did not significantly influence the outcome of HSCT. The choice of donor should be determined by the degree of HLA match and CMV status in preference to ABO blood group compatibility. Pediatr Blood Cancer 2007;49:313–317.

For many children with life-threatening hematological diseases, hematopoietic stem cell transplantation (HSCT) is the only curative option. In children lacking a matched related or unrelated donor and with the certainty that, left untreated, death will ensue alternative donors must be sought. Haplo-identical peripheral blood stem cell transplantation (PBSCT) from a healthy parent is a feasible alternative. To reduce the risk of fatal graft-versus-host disease (GvHD) as a complication of transplant across major histocompatibility antigens, intense T-cell depletion is required. Large numbers of purified, cytokine mobilized peripheral stem cells (the so-called mega-dose concept) are required to compensate for the significantly increased risk of either graft failure or early rejection. In our unit, despite this approach, graft dysfunction has, in a significant group of children, proved problematic and, despite salvage attempts at re-transplantation, usually fatal. In children with hematological malignant disease, our overall relapse-free survival is 41%. However, successful transplant outcome has been associated with considerable delays in immune reconstitution that can be implicated in subsequent viral reactivation. We are investigating new strategies to improve the outcome of haplo-identical PBSCT, which may allow us to offer this form of treatment to more children requiring urgent HSCT.

Candida albicans and non- C. albicans Candida species are increasingly being isolated from patients in high-risk categories, most notably, those who have undergone stem cell transplantation (SCT). Identification of the presence of non- C. albicans Candida species early in the course of the transplant procedure is important, as these species exhibit different sensitivities to the available antifungal treatments and cause mortality at rates that vary from those for C. albicans . Amplified fragment length polymorphism (AFLP) analysis has been shown to be a reliable method of reproducibly identifying medically important Candida species. We investigated the use of serial AFLP analysis of 54 routine surveillance cultures for the identification and epidemiological examination of Candida sp. colonization in five consecutive children undergoing allogeneic SCT. One child became colonized with a C. albicans strain and remained colonized with this strain during the whole admission period. Another child had persistent colonization with a C. albicans strain with striking variations in its AFLP patterns over time, which was considered indicative of microevolution. Candida dubliniensis , Candida lusitaniae , and Saccharomyces cerevisiae were identified in the three remaining patients, with two children being simultaneously and transiently colonized with different species. These findings show that colonization with yeasts during transplantation is a complex and dynamic interaction between the host and the organism(s). In our study three strains from eight separate time points were incorrectly identified as C. albicans by a rapid enzyme test. AFLP analysis of surveillance cultures allowed more accurate and informative epidemiological evaluations of pathogenic yeasts in children during transplantation.