New developments in the prophylaxis and treatment of graft versus host disease

Graft versus host disease (GVHD) remains the major obstacle to successful allogeneic bone marrow transplantation. Cyclosporin with methotrexate is the most common prophylactic regimen. Tacrolimus is associated with less GVHD and is gaining ground especially in unrelated donor transplants where current regimens are unsatisfactory. Mycophenolate mofetil (MMF) and rapamycin have not yet shown benefit in acute GVHD prophylaxis. In vivo T-cell depletion with Campath 1H or thymoglobulin used during transplant conditioning are increasingly used in place of ex vivo T-cell depletion, where results remain disappointing. Steroids remain first choice for therapy of GVHD but anti-CD25 antibodies, daclizumab or basiliximab are gaining popularity as second-line therapy ahead of ATG. Chronic GVHD is increasing with greater use of peripheral blood stem cell grafts and older patients. The combination of tacrolimus and MMF is promising for patients with extensive disease. Tolerance induction using CTLA-4-Ig, anti-CD40L, tresperimus and/or rapamycin may revolutionise GVHD therapy. However, due to the desirability of tumour intolerance, tolerance is likely to be developed in organ transplantation before bone marrow transplantation for traditional indications. Bone marrow transplants performed to induce organ tolerance may see increasing use of these agents. TNF blockade using infliximab or etanercept (Enbrel) is promising but the role of these agents is not yet defined.     

Monoclonal antibodies to treat graft-versus-host disease

To date, Graft-versus-host disease (GVHD) represents one of the most important complications of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is one of the major determinants of transplant-related mortality and it also may be an additional cause that affects patients late outcome. Despite of the development of new and advanced Human Leukocyte Antigens (HLA) matching techniques, this complication occurs in approximately 50-80% of patients who underwent allogeneic hematopoietic stem cell transplantation, and it is responsible for one-third of deaths after transplantation. Moreover, GVHD occurrence, if moderate, may strongly contribute to the eradication of residual malignant cells which survived after myeloablative conditioning regimen, allowing the patients to have a reduced risk of relapse so that the presence of this complication may have a determinant role for the allogeneic transplantation outcome through the so-called graft-versus-tumor (GVT) effect.     

Xenotransplantation: application of disease resistance

1. Organ transplantation is now clinically routine for patients with end-stage organ failure. One major limitation in transplantation is chronic rejection involving the loss of the graft despite the use of immunosuppressive agents. Haematopoietic stem cell (HSC) chimerism, achieved through bone marrow transplantation (BMT), induces donor-specific tolerance to transplanted organs and prevents chronic rejection. 2. A second major limitation to organ transplantation is the donor shortage. Xenotransplantation, the transplantation of organs between different species, would have the ability to increase the availability of donor organs. 3. Current immunosuppressive therapies do not prevent the rejection of xenografts. Therefore, the only reliable method for achieving donor-specific tolerance to xenografts may require HSC chimerism. 4. In order to justify the use of BMT to induce transplantation tolerance in patients with non-life-threatening diseases, the morbidity and mortality associated with current conditioning regimens must be addressed. 5. The use of partial conditioning regimens to promote engraftment of xenogeneic HSC and the development of donor-specific tolerance may eventually make xenotransplantation in humans a clinical reality. 6. Additional advantages of xenotransplantation are the ability to genetically engineer the donor xenograft and resistance of some xenografts to infection by human viruses because of the species specificity of most viruses. 7. The clinical application of disease resistance for HIV and hepatitis B virus is the focus of the present review.     

异基因骨髓移植和非清髓性干细胞移植嵌合形成过程的比较

目的 研究异基因骨髓移植（allo-BMT）和非清髓性干细胞移植（NST）两种移植方式在供体细胞嵌合状态的形成及转归上的差异,探讨早期供体细胞植入的关键因素。方法 对20例接受allo-BMT和18例NST的患者进行回顾性比较,研究两组患者疾病类型、干细胞来源、预处理方案和移植物抗宿主病预防方案。用复合扩增荧光标记STR-PCR结合毛细管电泳方法对移植后＋7、＋14、＋21d,＋1、＋3、＋6、＋9、＋12个月的嵌合体进行动态检测。结果 （1）NST组在受体年龄、单个核细胞（MNC）、CD34^＋及T细胞数量上均明显高于BMT组,造血重建方面,中性粒细胞绝对值恢复时间与BMT组无差别,但血小板恢复明显早于BMT组。（2）NST组患者供体细胞完全嵌合状态（FDC）的建立比BMT组早（1个月vs 3个月）,移植后早期（＋1个月）FDC比例亦明显高于BMT组（38．9％vs 20%）,而混合嵌合状态（MC）的发生率明显低于BMT组（61．2％ vs 80％）,移植1个月后各时间段两组在嵌合体形成上均无显著性差别。（3）氟达拉滨为基础的NST预处理方案与标准预处理方案相比并未延迟供体细胞的植入。（4）NST组慢性移植物抗宿主病的发生率明显高于BMT组（80％vs 50%,P〈0．01）,与NST组输入高剂量的CD34^＋细胞相关。结论 在供体细胞早期植入和嵌合体形成的过程中,移植物中造血干细胞和T细胞数量至关重要,并可能起决定性作用。     

贵州省首例半相合骨髓移植治疗急性白血病报告

目的 探讨半相合骨髓移植治疗急性白血病的疗效.方法 对1例男性47岁急性髓系白血病M2型患者采用半相合骨髓移植.预处理方案采用改良的BU/CY方案;GVHD的预防采用ATG+CSA+MMF +MTX方案;移植方式采用骨髓加外周血移植.结果 移植后19 d患者造血功能重建.移植后第30天、90天、180天行STR-DNA...     

The use of growth factors in hematopoietic stem cell transplantation

Mobilized, peripheral blood stem cells (PBSC) are increasingly used for both autologous and allogeneic transplants. Granulocyte-colony-stimulating factor is the most widely used cytokine for mobilization. Several different mechanisms of stem cell mobilization have been proposed including protease-dependent and non-protease- dependent mechanisms. In autologous transplants, the addition of chemotherapy to mobilization can enhance the yield of PBSC collected but with substantial adverse effects, and not necessarily faster engraftment. In allogeneic transplants, the use of mobilized PBSC is associated with faster engraftment and donor chimerism compared to bone marrow. In the majority of studies, the rate of acute graft-versus-host disease (GVHD) has not been shown to be significantly higher with PBSC, but the rate of chronic GVHD appears to be increased. Several different strategies have been proposed for patients and donors who fail initial mobilization, including the use of novel agents. AMD3100 (Plerixafor) works by directly inhibiting the interaction between stromal cell-derived factor-1 and its receptor CXCR4, and mobilizes hematopoietic stem cells within hours. It is being studied alone or in conjunction with growth factors for PBSC mobilization in both autologous and allogeneic settings. Although the use of growth factors after PBSC transplantation results in faster neutrophil engraftment its impact on treatment-related mortality and survival does not appear significant. Here, we review the biology and methods of PBSC mobilization, the effect of growth factors on normal donors and the controversies of growth factor use in the post-transplant setting. We also review the data on novel agents for mobilization of stem cells.     

Management of graft-versus-host disease in paediatric bone marrow transplant recipients

We discuss clinical strategies for the prophylaxis and treatment of both acute and chronic graft-versus-host disease (GVHD) with particular attention to children. Grades II to IV acute GVHD occur in 10 to 50% of patients given an allogeneic transplantation of haemopoietic stem cells (HSCT) from a genotypically HLA-identical donor. A significantly higher incidence and severity of the disease is reported in patients receiving transplants from partially matched family donors or unrelated volunteers. Younger individuals or patients receiving HSCT from younger donors develop GVHD less frequently than do older recipients. Severe acute GVHD is characterised by a significant decrease in survival probability, even though the graft-versus-leukaemia activity associated with both acute and chronic GVHD may reduce the risk of leukaemia relapse. Prophylaxis of acute GVHD usually consists of in vivo post-grafting immunosuppression with cyclosporin alone or in combination with methotrexate; methotrexate alone can be considered in leukaemia patients with a high risk of relapse. In recent years, tacrolimus is increasingly being used instead of cyclosporin, alone or in combination with methotrexate. In vitro T cell depletion in paediatric patients is usually reserved for those with transplants from partially matched family donors or unrelated volunteers. The treatment of patients with grades II to IV acute GVHD should be immediate and aggressive, as the quality and duration of the response directly correlates with survival. The overall response rate to treatment is often unsatisfactory, ranging from 40 to 50% of cases. First-line treatment usually consists of corticosteroids. In patients not responding to corticosteroids, antilymphocyte globulin and monoclonal antibodies directed towards lymphocytes and/or cytokines produced during GVHD are employed, but with variable success. Patients experiencing acute GVHD are also prone to develop chronic GVHD. whose classical treatment is based on the use of cyclosporin and corticosteroids. More recently, encouraging results in the treatment of patients with chronic GVHD have been reported with the use of extracorporeal photochemotherapy. Other drugs, such as ursodeoxycholic acid, etretinate and clofazimine, are under evaluation.     

Hematopoietic stem cell graft manipulation as a mechanism of immunotherapy

Hematopoietic stem cell transplants (SCT) are used in the treatment of neoplastic diseases, in addition to congenital, autoimmune, and inflammatory disorders. Both autologous and allogeneic SCT are used, depending on donor availability and the type of disease being treated, resulting in different morbidity and outcomes. In both types of SCT, immune regulation via graft manipulation is being studied, although with highly different targeted outcomes. In general, autologous SCT have lower treatment-related morbidity and mortality, but a higher incidence of tumor relapse, and graft manipulation targets immune augmentation and/or the reduction of immune tolerance. In contrast, allogeneic SCT have a higher incidence of treatment-related morbidity and mortality and a significantly longer time of disease progression, and the targeted outcomes or graft manipulation focus on a reduction in graft versus host disease (GVHD). One source of the increased relapse rate and shorter overall survival (OS) following high dose chemotherapy (HDT) and autologous SCT is the immune tolerance that limits host response, both innate and antigen (Ag) specific, against the tumor. The immune tolerance that is observed is due in part to the tumor burden and prior cytotoxic therapy. Therefore, graft manipulation, as an adjuvant therapeutic approach in autologous SCT, is primarily focused on non-specific or specific immune augmentation using cytokines and vaccines. Recently, manipulation of the infused product as a form of cellular therapy has begun to also focus on approaches to reduce immune tolerance found in transplant patients, both prior to and following HDT and SCT. To this end, graft manipulation to reduce the presence of Fas Ligand (FasL)-expressing cells or interleukin (IL)10 and tumor growth factor (TGF)beta production has been proposed.In contrast to autologous transplantation, graft manipulation during allogeneic transplantation is used extensively. This includes limiting the infusion of T cells within the product or as a donor leukocyte infusion (DLI), resulting in a reduction in GVHD and the induction of long-term survivors. Indeed, allogeneic SCT provide the only curative therapy for patients with chronic myelogenous leukemia (CML), refractory acute leukemia, and myelodysplasia. The curative potential of allogeneic SCT is reduced, however, by the development of GVHD, a potentially lethal T-cell-mediated immune response targeting host tissues [Int. Arch. Allergy Immunol. 102 (1993) 309, J. Exp. Med. 183 (1996) 589]. The morbidity and mortality associated with GVHD limit this technology, resulting focus on those patients who have no alternative therapeutic options or who have advanced disease. Thus, allogeneic SCT provide one of the few statistically supported demonstrations of therapeutic efficacy by T cells (comparison of allogeneic to autologous transplantation). In contrast to autologous transplantation, control of GVHD following allogeneic SCT focuses on immune suppression and the induction of tolerance. Here too, graft manipulation is appropriate, and there are numerous studies of T-cell depletion to reduce GVHD, with or without the isolation and infusion of T cells as DLI. Additional strategies are examining the isolation and infusion of T cells with graft versus leukemia (GVL) activity to reduce GVHD and/or the infusion of genetically manipulated and/or selected cellular populations (monocytes or dendritic cells (DC)) to induce tolerance. Therefore, depending upon the type of transplant, the goals associated with graft manipulation can be radically different. In this review, we emphasize using graft manipulation to regulate immune tolerance and anergy in association with SCT. Although this paper focuses on hematopoietic SCT, it should be noted that these strategies are relevant to conditions other than neoplastic and congenital diseases, including solid organ transplants, and autoimmune and inflammatory diseases.     

不同类型造血干细胞移植术后重型β-地中海贫血患儿长期生存质量情况

目的　了解同胞人类白细胞抗原（HLA）全合、非亲缘HLA全和及单倍体造血干细胞移植术后重型β-地中海贫血患儿长期生存质量情况。方法　选取2012—2019年于广西医科大学第一附属医院干细胞移植病区收治的不同移植类型的133例重型β-地中海贫血患儿为研究对象,其中男87例,女46例,平均年龄为5.39岁。使用单因素分析和多重线性回归分析重型β-地中海贫血患儿造血干细胞移植术后长期生存质量的相关因素。计量资料采用独立样本t检验或单因素方差分析,计数资料采用χ²检验。结果　133例重型β-地中海贫血患儿及其家长参与本次问卷调查。急性移植物抗宿主病（GVHD）发生率为14.3%（19/133）,慢性GVHD发生率为3.8%（5/133）。接受非亲缘HLA全合移植的患儿生活质量评分均较高,急性GVHD、慢性GVHD和合并症发生率均低于接受单倍体造血干细胞源移植的患儿（均P<0.05）。外周血干细胞移植（PBSCT）或脐血干细胞移植（UCBT）、PBSCT+骨髓移植（BMT）、BMT、BMT+UCBT均对生活质量无明显影响（均P>0.05）。单因素分析表明年龄（B=-3.234,P<0.001）、慢性GVHD（B=-19.452,P=0.001）、并发症（B=-23.327,P<0.001）和移植时长（B=13.369,P<0.001）与移植后重型β-地中海贫血患儿生活质量相关,其他因素如性别、移植物类型、供者类型、HLA是否相合、供受者血型是否相合、GVHD预防方案、急性GVHD与患儿生活质量均无显著相关性（均P>0.05）。多元线性回归分析表示患儿年龄越大、并发症种类越多,患儿移植后生活质量越差,而随着移植后时间延长,患儿生活质量越好（均P<0.05）。结论　有合适供者重型地中海贫血患儿尽早进行异基因造血干细胞移植,注重控制移植并发症,保证患儿移植后生活质量。     

CM-DiI labeled mesenchymal stem cells homed to thymus inducing immune recovery of mice after haploidentical bone marrow transplantation

The results of haploidentical hematopoietic stem cell transplantation (HSCT) have been disappointing due to the high incidence of severe graft-versus-host disease (GVHD) and infectious complications. It is well known that mesenchymal stem cells (MSCs) can prevent severe acute GVHD in HSCT. However, there is a controversy concerning whether MSC-mediated suppression of T cell functions is accompanied by inducing T cells maturation effects after HSCT. The CB6F1((H-2bd)) female mice irradiated with 8 Gy (60)Co γ-rays were divided into two groups: mice in the MSCs group were infused with MSCs labeled with cm-DiI and mononuclear cells from the bone marrow and spleen of BALB/c((H-2d)) mice; the control group was infused with only the mononuclear cells of BALB/c((H-2d)) mice. After transplantation, chimerisms of donor MSCs were observed in the recipients. The recovery of the T-lymphocyte subpopulation, the proliferative activity of T-cells after stimulation with ConA, the mixed lymphocytes' reaction between donor and recipient and three parts, and the number of apoptosis thymus cells were compared in two groups. The results showed that MSCs preferentially homed to the thymus and grew there, a more rapid recovery of T-cells in the peripheral blood, and decreased the apoptosis of the thymocytes. Thus MSCs may affect the thymus in order to improve T-cells maturation and immune system recovery.     

Embryonic stem cell-derived hematopoietic stem cells: challenges in development, differentiation, and immunogenicity

Embryonic stem cells (ESC) can potentially be manipulated in vitro to differentiate into cells and tissues of all three germ layers. This pluripotent feature is being exploited to use ESC-derived tissues as therapies for degenerative diseases and replacement of damaged organs. Although their potential is great, the promise of ESC-derived therapies will be unfulfilled unless several challenges are overcome. For example, inefficient production of ESC-derived tissues before transplantation, inability of ESC-derived tissues to integrate well into the adult microenvironments due to developmental stage incompatibility, or active immune rejection of the ESC-derived graft are all potential challenges to successful ESC-derived therapies. One way to induce immunological tolerance to allogeneic tissues is via the establishment of mixed hematopoietic chimerism in which the host and donor cells are educated to recognize each other as "self". Proof of principle that in vitro cultured ESC-derived hematopoietic progenitors can be transplanted and induce immunological tolerance to allogeneic tissues exists in mouse models. In this review, we discuss the challenges to in vitro development of a bona fide ESC-derived hematopoietic stem cell and their differentiation fate in vivo, and provide suggestions to predict the immunogenicity of specific ESC-derived hematopoietic populations before transplantation that could be used to prevent their rejection after transplantation into an adult host.     

Intravenous busulfan: in the conditioning treatment of pediatric patients prior to hematopoietic stem cell transplantation

An intravenous formulation of busulfan, a cytotoxic bifunctional alkylating agent, has been developed to replace oral busulfan as a conditioning treatment prior to hematopoietic stem cell transplantation (HSCT) in pediatric patients. Doses of intravenous busulfan based on actual bodyweight, but not age, reduce inter- and intraindividual variability in exposure. In a study of intravenous busulfan as a conditioning treatment prior to allogeneic or autologous HSCT, the majority of pediatric patients, who received one of five bodyweight-based doses, achieved busulfan area under the plasma concentration-time curve (AUC) values within the targeted therapeutic range. Although mean busulfan clearance values were highly variable between bodyweight strata, exposure was not affected, with no significant differences between bodyweight groups in mean AUC values. The achievement of therapeutic AUC values with intravenous busulfan resulted in a high rate of sustained engraftment, low transplant-related mortality, and promising survival outcomes post-transplant. Intravenous busulfan was considered to be well tolerated, in the particular context of HSCT, and no failure of HSCT due to organ toxicity was reported. Nonhematologic adverse events commonly associated with busulfan conditioning regimens were frequent, but generally of mild to moderate severity. The intravenous busulfan regimen was frequently associated with elevated liver enzymes, but hepatic veno-occlusive disease (HVOD) was infrequent, of mild to moderate severity, and resolved within 10 days of diagnosis. Unlike oral busulfan, intravenous busulfan does not appear to be associated with severe HVOD or death due to organ toxicity.     

OTI-010 Osiris Therapeutics/JCR Pharmaceuticals

Osiris Therapeutics is developing the donor-derived mesenchymal stem cell (MSC) therapy OTI-010, which repopulates the bone marrow stroma and thus supports engraftment of hematopoietic stem cells from the same donor. This stem cell therapy, which has been awarded Orphan Drug status, is currently in development for the potential enhancement of bone marrow transplants in cancer patients, for the prevention of graft versus host disease (GVHD), and for the treatment of Crohn's disease. Japanese licensee JCR Pharmaceuticals is investigating the therapy for the potential treatment of GVHD in patients undergoing bone marrow transplantation to treat leukemia. Phase II clinical trials in acute gastrointestinal GVHD and in adult and pediatric patients with treatment-refractory severe GVHD are currently underway.     

Links Between Cyclosporin Exposure in Tissues and Graft-<Emphasis Type="Italic">Versus</Emphasis>-Host Disease in Pediatric Bone Marrow Transplantation: Analysis by a PBPK Model

Purpose  

In hematopoietic stem cell transplantation (HSCT), cyclosporin is used to prevent graft-versus-host disease (GVHD). However, cyclosporin distribution in tissues is not linear, resulting in uncertainty regarding optimal dosing and monitoring. The objective of this study was to link the probability and severity of acute GVHD to cyclosporin exposure in blood, GVHD target organs, and lymphoid organs.     

Human umbilical cord blood biology, transplantation and plasticity

As the significance of hematopoietic stem cell transplantation (HSCT) is constantly rising, the scarcity of matched donors is proving to be a troubling issue. Cord blood (CB) is an important source of stem cells (SC) for transplantation. It has been used in the last two decades for approximately 4500 transplantations. Its collection, cryopreservation, banking and thawing techniques pose unique challenges to clinicians and researchers CB has abundant stem cell with impressive proliferative capacity. On the other hand, CB's immunological system has a na?ve and more tolerant nature. Except for the biological aspects, few ethical issues have become a concern for transplantation teams who use CB. There are few advantages of CB over bone marrow, especially the lower rates of acute and chronic graft-versus-host disease (GVHD) after transplantation. On the other hand, there are relatively high rates of early treatment related mortality in cord blood transplantation (CBT). This is related to the small nucleated cell (NC) dose infused from each CB unit. The clinical experience in CBT, especially in children, is encouraging. When using adequate number of NC/kg, results in CBT for malignant and non-malignant diseases are comparable to bone marrow transplantation (BMT). In this article, a comprehensive review of the largest scale studies is presented. There is a continuous search for an optimal way to deal with delayed engraftment of CB and its implication. The current investigational, and also first clinical trials using diverse methods to overcome high rates of TRM are reviewed. Almost twenty years after the first CBT was preformed, many advocate for a routine parallel search, BM and CB, for unrelated donor. Future uses of CB might also be in the field of gene transfer and non hematopoietic injured tissues repair.     

Emerging therapies for graft-versus-host disease

Acute graft-versus-host disease (GVHD) and chronic GVHD remain the major barriers to successful haematopoietic cell transplantation. The induction of GVHD may be divided into three phases: (i) recipient conditioning, (ii) donor T cell activation, and (iii) effector cells mediating GVHD. Standard agents and agents under development to prevent and treat GVHD are discussed. The various pharmacological agents impact on different phases of the GVHD cascade. Sirolimus is a new immunophilin binding agent that appears to be synergistic with tacrolimus and cyclosporin. It also seems to promote allograft tolerance. Mycophenolate mofetil (MMF) is an antimetabolite that is currently under study for prophylaxis and treatment of acute and chronic GVHD; results are encouraging. Other agents such as the purine analogue pentostatin and the monoclonal antibodies alemtuzumab, daclizumab and infliximab are discussed at length within the GVHD context. The most effective approach to GVHD prevention will likely be a combination regimen where the three phases of the GVHD cascade are disrupted. Once GVHD has occurred, all three phases of the cascade are activated. Developments of combination therapy for the treatment of both acute and chronic GVHD will likely yield better results than monotherapy. The numerous new treatment modalities presented should improve the outlook for acute and chronic GVHD.     

亲属活体肾和造血干细胞联合移植诱导免疫耐受研究

目的探讨亲属活体肾造血干细胞联合移植诱导免疫耐受的可行性及安全性。方法对3例女性尿毒症患者进行亲属活体肾造血干细胞联合移植（观察组） 同期接受亲属活体肾移植的5例女性尿毒症患者作为对照组。供体均为男性。采用PCR-SRY方法进行嵌合体检测。测定受体淋巴细胞亚群,随访观察肾造血干细胞联合移植的并发症和临床移植效果并与对照组进行比较分析。结果观察组嵌合体阳性率100%,对照组60% 观察组肾移植受者临床效果良好,呈现免疫低反应和免疫抑制趋势。结论亲属活体肾造血干细胞联合移植是一种可行的诱导免疫耐受的方法,可以诱导产生临床肾移植的免疫低反应。     

Cell transplantation for endocrine disorders

Current hormonal replacement therapy for endocrine disorders cannot, unfortunately, reproduce the complex metabolic interactions of hormones. The organ or cell transplantation would be a more physiological approach to the treatment of endocrine disorders. For decades, remarkable progress in organ or cell transplantation in endocrine disorders has been made, especially in recent years. But there are many limitations in the widespread application of allotransplantation because of rejection. Various methods of immunomanipulations designed to overcome rejection have been proposed, which include immunosuppression, immunomodulation and immunoisolation. The transplantation of immunoisolated cells and some clinical results of the transplants were reviewed. Also a perspective for future directions on endocrine cell transplantation was provided in this review. Human islet cell transplantation for the cure of diabetes was emphasized in this chapter and other cell transplantation for endocrine disorders was also discussed briefly, including parathyroid tissue transplantation, bioartificial thyroid transplantation and adrenal cell transplantation.     

Induction of transplantation tolerance via regulatory T cells

In the last two decades, graft survival has been greatly improved by the introduction of efficient immunosuppressive drugs. On the other hand, late graft loss caused by chronic rejection together with the side effects of long-term immunosuppression, remain major obstacles for successful transplantation. Operational tolerance, which is defined by the lack of acute and chronic rejection and indefinite graft survival with normal graft function in the absence of chronic immunosuppression, represents an attractive alternative. Several approaches have been explored to achieve transplantational tolerance, which is considered the "Holy Grail" of transplantation, including induction of central tolerance by establishing mixed chimerism through hematopoietic stem cell transplantation or induction of peripheral tolerance through modulation of allogeneic immune responses. Graft-specific alloreactive T cells, which largely mediate graft rejection, can be silenced through different mechanisms, including deletion, which may occur within the thymus or in the lymphoid organs; anergy, in which alloreactive T cells cannot adequately respond following restimulation with the specific antigen; and suppression, which may be mediated by direct interactions with regulatory T cells (Tregs) or by soluble factors produced by Tregs. This review attempts to summarize the most novel and successful strategies to achieve operational tolerance via induction of Tregs.     

Non-pharmacologic strategies in hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) may be performed to treat a variety of malignant and non-malignant disorders by eradicating tumor, replacing a non-functioning with a normal immune system, or replenishing a deficient enzyme. While HSCT may provide cure for many patients, barriers such as acute and chronic graft-versus-host disease (a/cGVHD) and graft failure continue to challenge clinicians with considerable potential for morbidity and mortality. A thorough understanding of each disease process is essential to the development of both pharmacologic and non-pharmacologic therapies in this setting; unfortunately, acute and chronic GVHD, are distinct, complex entities, and medications used to prevent and treat them cause significant toxicities and leave patients at high risk for overwhelming infections. Standard pharmacologic therapies that are currently in use are limited in that they have the potential to cause significant toxicity without completely curing the disease. Novel, non-pharmacologic therapies for the prevention and treatment of acute and chronic GVHD must continue to be developed and studied in randomized trials. Given that the potential mechanisms of action of the non-pharmacologic therapies discussed herein attempt to modulate the cellular milieu that supports the development of GVHD, a brief discussion of GVHD and its pathophysiology is warranted; detailed discussions are provided by Cutler et al. and Bolanos-Meade elsewhere in the current issue. We will therefore focus on two non-pharmacological innovative forms of therapy, and potentially, prevention of GVHD.