Adoptive transfer of T-cell precursors enhances T-cell reconstitution after allogeneic hematopoietic stem cell transplantation

Immunoincompetence after allogeneic hematopoietic stem cell transplantation (HSCT) affects in particular the T-cell lineage and is associated with an increased risk for infections, graft failure and malignant relapse. To generate large numbers of T-cell precursors for adoptive therapy, we cultured mouse hematopoietic stem cells (HSCs) in vitro on OP9 mouse stromal cells expressing the Notch-1 ligand Delta-like-1 (OP9-DL1). We infused these cells, together with T-cell-depleted mouse bone marrow or purified HSCs, into lethally irradiated allogeneic recipients and determined their effect on T-cell reconstitution after transplantation. Recipients of OP9-DL1-derived T-cell precursors showed increased thymic cellularity and substantially improved donor T-cell chimerism (versus recipients of bone marrow or HSCs only). OP9-DL1-derived T-cell precursors gave rise to host-tolerant CD4+ and CD8+ populations with normal T-cell antigen receptor repertoires, cytokine secretion and proliferative responses to antigen. Administration of OP9-DL1-derived T-cell precursors increased resistance to infection with Listeria monocytogenes and mediated significant graft-versus-tumor (GVT) activity but not graft-versus-host disease (GVHD). We conclude that the adoptive transfer of OP9-DL1-derived T-cell precursors markedly enhances T-cell reconstitution after transplantation, resulting in GVT activity without GVHD.     

Plasticity after allogeneic hematopoietic stem cell transplantation

The postulated almost unlimited potential of transplanted hematopoietic stem cells (HSCs) to transdifferentiate into cell types that do not belong to the hematopoietic system denotes a complete paradigm shift of the hierarchical hemopoietic tree. In several studies during the last few years, donor cells have been identified in almost all recipient tissues after allogeneic HSC transplantation (HSCT), supporting the theory that any failing organ could be accessible to regenerative cell therapy. However, the putative potential ability of the stem cells to cross beyond lineage barriers has been questioned by other studies which suggest that hematopoietic cells might fuse with non-hematopoietic cells and mimic the appearance of transdifferentiation. Proof that HSCs have preserved the capacity to transdifferentiate into other cell types remains to be demonstrated. In this review, we focus mainly on clinical studies addressing plasticity in humans who underwent allogeneic HSCT. We summarize the published data on non-hematopoietic chimerism, donor cell contribution to tissue repair, the controversies related to the methods used to detect donor-derived non-hematopoietic cells and the functional impact of this phenomenon in diverse specific target tissues and organs.     

The role of virus-specific adoptive T-cell therapy in hematopoietic transplantation

Viral infections are amongst the most significant complications following hematopoietic transplantation and occur principally because of a lack of virus-specific T cells. Drug treatments are often suboptimal because of toxicity, limited viral sensitivity, or the potential for the development of resistance. Adoptive immunotherapy to restore virus-specific cellular immunity is clearly an attractive alternative and the pioneering work of the previous decade established that cellular products could be clinically effective. However, the techniques used in these early studies are expensive and relatively difficult to produce to GMP-compliant standards. This is major limitation to their wider application. This review concentrates on more recent studies detailing direct selection methodologies that are more suited to clinical scalability and more readily assessable in prospective randomised studies. We will also consider strategies that allow multiple pathogens to be targeted concurrently, and strategies that aim to extend the benefits of these technologies to transplant recipients whose donors are seronegative for these viruses and currently are most vulnerable to viral reactivations.     

The time is now: moving toward virus-specific T cells after allogeneic hematopoietic stem cell transplantation as the standard of care

Adoptive immunotherapy—in particular, T-cell therapy—has recently emerged as a useful strategy with the potential to overcome many of the limitations of antiviral drugs for the treatment of viral complications after hematopietic stem cell transplantation. In this review, we briefly summarize the current methods for virus-specific T-cell isolation or selection and we report results from clinical trials that have used these techniques, focusing specifically on the strategies aimed to broaden the application of this technology.     

Diagnosis and treatment of viral diseases in recipients of allogeneic hematopoietic stem cell transplantation

Viral infections are important causes of morbidity and mortality after allogeneic stem cell hematopoietic transplantation (allo-HSCT). Although most viral infections present with asymptomatic or subclinical manifestations, viruses may result in fatal complications in severe immunocompromised recipients. Reactivation of latent viruses, such as herpesviruses, is frequent during the immunosuppression that occurs with allo-HSCT. Viruses acquired from community, such as the respiratory and gastrointestinal viruses, are also important pathogens of post-transplant viral diseases. Currently, molecular diagnostic methods have replaced or supplemented traditional methods, such as viral culture and antigen detection, in diagnosis of viral infections. The utilization of polymerase chain reaction facilitates the early diagnosis. In view of lacking efficacious agents for treatment of viral diseases, prevention of viral infections is extremely valuable. Application of prophylactic strategies including preemptive therapy reduces viral infections and diseases. Adoptive cellular therapy for restoring virus-specific immunity is a promising method in the treatment of viral diseases.     

Heterogeneous impact of cytomegalovirus reactivation on nonrelapse mortality in hematopoietic stem cell transplantation

This study aims to retrospectively analyze the efficacy of penciclovir in the prevention of viral infection after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Ninety-six patients with allo-HSCT were enrolled, who were treated at the Medical Center of Hematology of Xinqiao Hospital from June 2020 to September 2021. The experimental and control groups were treated with penciclovir and acyclovir, respectively, to prevent viral infection. By February 2022, the infection rates of cytomegalovirus, BK virus, JC virus, and Epstein-Barr virus (EBV) in the experimental group and the control group were 18.8% and 39.06% (P<0.05), 28.1% and 25% (P>0.05), 6.2% and 7.81% (P>0.05), 21.8% and 23.43% (P>0.05), respectively. The infection-related urinary system symptoms of the experimental group and the control group occurred in 4 and 9 patients, respectively, of which 3 and 9 patients died, respectively. Penciclovir can significantly reduce the cytomegalovirus infection rate after allo-HSCT and has better preventive effects than acyclovir without obvious side effects. The effectiveness and safety of penciclovir will be further verified in the future.     

Reconstitution of adaptive and innate immunity following allogeneic hematopoietic stem cell transplantation in humans

Allogeneic hematopoietic stem cell transplantation is a potentially curative treatment modality for a number of hematologic malignancies, as well as inherited immunodeficiencies and hemoglobinopathies, and may also have a role in selected acquired autoimmune disorders. The complete or near-complete ablation of host immunity and subsequent establishment of donor-derived immunity that is required for successful engraftment and long-term outcomes provide a major obstacle to such transplantation approaches. A delicate balance exists between the need for the reconstituted donor-derived immunity to provide both protection against pathogenic challenges and graft-versus-malignancy activity, and the potentially harmful expansion of alloreactive T-cell clones mediating GvHD. The search for interventions that would allow more rapid and selective reconstitution of beneficial immune specificities continues to be informed by the development of new tools enabling a more precise dissection of the kinetics of reconstituting populations. This review summarizes more recent data on immune reconstitution following allogeneic transplantation in humans.     

Determining Toxoplasma high-risk autologous and allogeneic hematopoietic stem cell transplantation patients by systematic pre-transplant PCR screening of stem cell originated buffy coat

The diagnosis of Toxoplasma infection or disease in hematopoietic stem cell transplantation (HSCT) patients is achieved mainly by PCR screening; however screening did not find wide field of use in practice due to costly expenditures of PCR. This study aimed to determine patients at high risk of Toxoplasma infection or disease before transplantation by stem cell originated buffy coat PCR and subsequently to screen them. Buffy coats collected from 12 autologous and 18 allogeneic HSCT patients' donors were investigated by PCR before transplantation. After transplantation, blood and sera collected at fixed time intervals were screened by two PCR methods and serological assays. Screening results first time assessed a toxoplasmosis incidence level as 25% in autologous HSCT patients and increased incidence level in allogeneic HSCT patients to 22%. Importantly, buffy coat PCR was first time performed before transplantation, to determine the risk of toxoplasmosis. Buffy coat PCR results showed that four patients were at high risk of toxoplasmosis before transplantation. After transplantation, these patients experienced toxoplasmosis. In conclusion, for the determination of patients at risk of toxoplasmosis, clinicians should consider buffy coat PCR in combination with serology before transplantation. After transplantation, PCR screening can be initiated in high risk patients upon clinical suspicion.     

G-CSF诱导移植物抗白血病效应治疗异基因造血干细胞移植后复发白血病的研究

目的观察应用G-CSF诱导移植物抗白血病效应治疗异基因造血干细胞移植后复发白血病的疗效。方法对2011年7月至2013年2月该科异基因造血干细胞移植后40例复发的白血病患者,进行输注粒细胞集落刺激因子动员后供者外周血单个核细胞治疗。其中-CR3髓系有4例,细胞混合有6例,-CR2淋巴细胞有10例,-CR2髓系有16例,髓系加速期慢性有4例。在异基因造血干细胞移植后,半年内,40例患者均复发,予G-CSF动员后,供者外周血单个核细胞输注,每次输注细胞量逐级增加,每次输注间隔4周。结果 24例患者再次缓解完全,未缓解的16例。患者输注后,6例发生急性移植物抗宿主病Ⅰ~Ⅱ度,24例发生慢性移植物抗宿主病,5例未发生并发症。结论 G-CSF诱导移植物抗白血病效应治疗后,白血病复发有较好的疗效,不良反应小,值得临床推广。     

异基因造血干细胞移植后并发自身免疫性溶血性贫血的治疗进展

异基因造血干细胞移植（HSCT）后自身免疫性溶血性贫血（AIHA）是HSCT后并不少见的并发症,其发病率约1﹪~ 6﹪,不同于一般的AIHA,HSCT后AIHA发病机制尚未完全明确,可能与HSCT后受者体内免疫失调相关。危险因素与移植患者年龄小、非恶性疾病、使用无关供者、半相合供者移植、脐血移植、去T细胞移植及移植后并发慢性移植物抗宿主病（GVHD）等有关。皮质激素作为一线治疗,疗效有限,难以持续缓解,需联合使用利妥昔单抗（RTX）、大剂量丙种球蛋白等,甚至需要联合霉酚酸酯、环磷酰胺、西罗莫司、阿伦单抗、依库丽单抗或蛋白酶体抑制剂硼替佐米等免疫抑制剂治疗,部分患者需行血浆置换,偶有行脾切除术者。移植后AIHA总死亡率常高达50﹪,总体预后差于单纯AIHA。该综述旨在总结HSCT后并发AIHA的最新治疗进展,供临床医师参考。     

Dendritic cell vaccination in an allogeneic stem cell recipient receiving a transplant from a human cytomegalovirus (HCMV)-seronegative donor: induction of a HCMV-specific Thelper cell response

Background aimsIn the absence of a protective immune response, human cytomegalovirus (HCMV) infection remains a life-threatening complication after allogeneic stem cell transplantation (SCT), especially in recipients of grafts from HCMV-seronegative donors. After allogeneic SCT from a seronegative donor, prolonged and severe immune deficiency often leads to infectious complications. Vaccination with antigen-loaded dendritic cells (DC) has been shown to be a potent approach for the induction of antigen-specific cytotoxic T-cell responses in vivo. For protection from subsequent HCMV reactivation, a sustained immune response is necessary, including antigen-specific CD4⁺ T cells.MethodsWe report the case of an 18-year-old girl with high-risk acute lymphoblastic leukemia that received an allogeneic SCT in CR2. After an HCMV infection, the graft was rejected and she received a second transplant from an HLA-mismatched, HCMV-seronegative family donor. She was treated with pp65-pulsed monocyte-derived DC at day 200 post-SCT, using a recombinant pp65 protein. Until day 200 post-SCT, HCMV reactivated six times with emerging viral resistance to antiviral chemotherapy.ResultsAfter vaccination with protein-pulsed DC, an induction and expansion of HCMV-specific T_helper cells and cytotoxic T lymphocytes was observed, associated with a sustained clearance of the HCMV viremia. Antiviral treatment could be tapered without recurrence of viremia within the first year post-SCT.Conclusionspp65-pulsed DC could induce antigen-specific T-cell responses even after a SCT from an HCMV-seronegative donor. After vaccination with pp65-pulsed DC, a sustained antigen-specific T-cell response prevented concurrent HCMV viremia. Emergence of antigen-specific T_helper cells may be essential for a sustained, functional T-cell response post-SCT.     

Mesenchymal stem cells in hematopoietic stem cell transplantation

Mesenchymal stromal/stem cells (MSC) of bone marrow (BM) origin not only provide the supportive microenvironmental niche for hematopoietic stem cells (HSC) but are capable of differentiating into various cell types of mesenchymal origin, such as bone, fat and cartilage. In vitro and in vivo data suggest that MSC have low inherent immunogenicity, modulate/suppress immunologic responses through interactions with immune cells, and home to damaged tissues to participate in regeneration processes through their diverse biologic properties. MSC derived from BM are being evaluated for a wide range of clinical applications, including disorders as diverse as myocardial infarction and newly diagnosed diabetes mellitus type 1. However, their use in HSC transplantation, either for enhancement of hematopoietic engraftment or for treatment/prevention of graft-versus-host disease, is far ahead of other indications. Ease of isolation and ex vivo expansion of MSC, combined with their intriguing immunomodulatory properties and their impressive record of safety in a wide variety of clinical trials, make these cells promising candidates for further investigation.     

The role of nutrition and effects on the cytokine milieu in allogeneic hematopoietic stem cell transplantation

Nutritional deficiency is very common after allogeneic stem cell transplantation (HSCT) despite careful assessment and nutritional supplementation (total parenteral or oral nutrition). The importance of nutrition in the immune system has been well defined during the past several years, as it has modulatory effects on the immune system. One of the most frequent questions in nutrition is whether nutritionally at-risk hosts have a defect in their immune system and whether such defects can be corrected by nutritional supplementation. Addressing nutritional supplementation starting from early post-transplantation might decrease the risk of infectious complication and GVHD after HSCT via the immunomodulatory role of a variety of nutrients and supplements. Given the well-established link between nutrition and immunomodulation, we hypothesize that timely nutritional supplementation can potentially play a direct or indirect role in decreasing non-relapse morbidity and mortality after HSCT. In this article, we discuss the possible link between nutritional deficiency and its effects on the cytokine milieu after HSCT.     

Potential of glycosylation research in graft versus host disease after allogeneic hematopoietic stem cell transplantation

BackgroundGlycans, complex oligosaccharides, are directly involved in almost every biological process, have a fundamental role in the immune system, and are probably involved in nearly every human disease. However, glycosylation has been greatly ignored in the area of allogeneic hematopoietic stem cell transplantation (alloHSCT) and graft versus host disease (GVHD). Both acute and chronic GVHD are multisystemic debilitating immunological disturbances arising after alloHSCT.Scope of reviewIn this paper, we review the glycosylation research already done in the field of alloHSCT and GVHD and evaluate further potential of glycan analysis in GVHD by looking into resembling inflammatory and autoimmune conditions.Major ConclusionsGlycan research could bring significant improvement in alloHSCT procedure with reduction in following complications, such as GVHD. Identifying glycan patterns that induce self-tolerance and the ones that cause the auto- and allo-immune response could lead to innovative and tissue-specific immunomodulative therapy instead of the current immunosuppressive treatment, enabling preservation of the graft-versus-tumor effect. Moreover, improved glycan pattern analyses could offer a more complete assessment and greatly needed dynamic biomarkers for GVHD.General significanceThis review is written with a goal to encourage glycan research in the field of alloHSCT and GVHD as a perspective tool leading to improved engraftment, discovery of much needed biomarkers for GVHD, enabling an appropriate therapy and improved monitoring of therapeutic response. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc.