The prevention and treatment of cytomegalovirus infection in haematopoietic stem cell transplantation

Allogeneic haematopoietic stem cell transplantation (HSCT) is an intensive medical treatment involving myeloablative chemo-radiotherapy followed by stem cell rescue using allogeneic haematopoietic stem cells harvested from HLA-matched donors, which is primarily used for the treatment of haematological malignancies. Cytomegalovirus (CMV) infection is one of the major causes of morbidity and death after HSCT. This focused research review highlights the advances made with research into CMV in the HSCT setting. It provides the reader with an overview of current CMV research into the prevention and management of CMV infection. This paper is a Focussed Research Review from the meeting which took place 28–29 May 2008 in Nottingham, UK, celebrating the contribution of Prof. I. A. “Tony” Dodi (+29.1.2008) to the EU project “Network for the identification and validation of antigens and biomarkers in cancer and their application in clinical tumour immunology (ENACT)”.     

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.     

Allogeneic peripheral blood stem cell transplantation

Granulocyte colony stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSC) are now widely used instead of bone marrow for autologous transplantation due to earlier hematopoietic recovery after transplant. The low toxicity of G-CSF has prompted phase I and II studies to evaluate PBSC for allogeneic transplantation; these studies have demonstrated that engraftment of neutrophils, red blood cells and platelets is faster with peripheral blood cells compared to marrow. In randomized studies comparing mobilized PBSC and marrow for allogeneic transplantation, most trials have confirmed significantly earlier engraftment with PBSC and similar risks of acute graft-vs.-host disease (GVHD). In some trials, an increase of 10-15% in grade II-IV GVHD has been noted with PBSC. All studies showed a trend towards more chronic GVHD with PBSC. Some randomized studies have shown improved survival and disease-free survival with the use of PBSC due to lowered transplant-related mortality and fewer relapses in recipients of PBSC as a result of improved immune reconstitution and a graft-vs.-leukemia (GVL) effect. This survival benefit is most apparent in patients with more advanced hematologic malignancies, but further studies are needed to define the relative benefits of PBSC for patients with less advanced disease. The GVL effect of PBSC is currently being exploited with the use of non-ablative allografts.     

Hematopoietic stem cell transplantation in SCD

Hematopoietic stem cell transplantation (HSCT) is the one and only curative therapy available for patient with severe sickle cell disease (SCD). Until today, several hundreds of patients have undergone geno-identical HSCT. More than 200 patients were transplanted in France. The first indication was cerebral vasculopathy. Among both malignant and non-malignant diseases treated with HSCT, the success rate obtained in SCD patients appears as the best one. From the year 2000, more than 95% of transplanted patients survived the HSCT procedure and more than 90% are completely cured and experience a very satisfying health condition post-transplantation. However, the current standard procedure includes a myeloablative conditioning regimen for warranting engraftment. Such regime is linked to severe long-term side effects such as hypofertility. Due to the excellent obtained results, we have to think about a possible widening of indications, a decrease of conditioning intensity and toxicity, and about HSCT from alternative stem cell sources, such as mismatch family donor, unrelated volunteer donor or unrelated cord blood.     

Hematopoietic stem cell transplantation for thalassemia

Hematopoietic stem cell transplantation (HSCT) represents the only cure for patients with thalassemia. At present HSCT in younger patients from an HLA- matched sibling donor offers 80% to 87% probability of cure according to risk classes. However, results HSCT in adult patients continue to be inferior due to advanced of disease. High-resolution tissue typing techniques have enabled transplant centres to offer allogeneic HSCT from unrelated donors to patients with thalassemia who could not benefit from matched sibling donor transplantation with results comparable to those obtained using sibling donors. Advances in transplantation biology have made it possible to perform haploidentical HSCT in patients with thalassemia who lack a related or unrelated matched donor. Although limited number of patients, results of unrelated cord blood transplantation for thalassemia are encouraging. Patients with graft failure could now benefit from second transplantation using the same donor with a high disease-free survival rate. Most ex-thalassemics continue to have disease and treatment-related complications acquired before transplantation which require adequate treatment following BMT.     

Potential risk of infection transmission during storage and transplantation of hematological progenitor cells. Safety assurance

In a group of 71 patients and 22 donors the danger of infection transmission by infusion of cryopreserved peripheral blood progenitor cells to the patient and/or cross contamination of stored grafts was evaluated. No laboratory signs of active infection were found in 15 donors (13 related, 2 unrelated; 68%) and in 55 patients (77%). Active infection by herpesviruses was the most common (in 13 patients and 7 donors), hepatitis B being found in only one case. The cytomegalovirus IgG test was the most common marker of previous infection; it was found in 14 donors and 55 patients. The rate of clinically unsuspected infections in donors and patients including cases requiring immediate treatment among the patients group is relatively high and fully justifies the practice of prophylactic serological testing in the whole range of tests according to the European Blood and Marrow Transplantation Group and International Society for Hematotherapy and Graft Engineering in both autologous and allogeneic transplantations of hematopoietic stem cells.     

Spermatogonial stem cell transplantation and testicular function

Spermatogonial stem cells (SSCs) are responsible for the continual production of spermatozoa throughout adult life. Interactions between SSCs and the surrounding cells in the seminiferous tubules regulate the biological activity of these cells. Factors involved in the regulation of SSCs are beginning to be defined by animal models and the culture of SSCs in defined media. A critical development in the characterization of SSCs has been the development of the germ cell transplantation technique, which provides the only assay for the presence of SSCs in a population of cells, and which allows the determination of whether SSCs are proliferating or differentiating in culture. This approach has accelerated SSC-focused research and promises to provide a better understanding of the factors and mechanisms that regulate these cells. The knowledge provided by this work is also critical to an appraisal of the components of the SSC niche in the seminiferous epithelium. Thus, many aspects of testicular function can be defined by the investigation of SSCs and the factors, cells, and environment that regulate SSCs, thereby leading to a more comprehensive understanding of spermatogenesis.     

Autologous stem cell transplantation for myocardial repair

Current therapies for heart failure due to transmural left ventricular (LV) infarction are limited. We have developed a novel patch method for delivering autologous bone marrow stem cells to sites of myocardial infarction for the purpose of improving LV function and preventing LV aneurysm formation. The patch consisted of a fibrin matrix seeded with autologous porcine mesenchymal stem cells labeled with lacZ. We applied this patch to a swine model of postinfarction LV remodeling. Myocardial infarction was produced by using a 60-min occlusion of the left anterior descending coronary artery distal to the first diagonal branch followed by reperfusion. Results were compared between eight pigs with stem cell patch transplantation, six pigs with the patch but no stem cells (P), and six pigs with left anterior descending coronary artery ligation alone (L). Magnetic resonance imaging data collected 19 +/- 1 days after the myocardial infarction indicated a significant increase of LV systolic wall thickening fraction in the infarct zone of transplanted hearts compared with P or L hearts. Blue X-gal staining was observed in the infarcted area of transplanted hearts. PCR amplification of specimens from the X-gal-positive area revealed the Ad5 RSV-lacZ vector fragment DNA sequence. Light microscopy demonstrated that transplanted cells had differentiated into cells with myocyte-like characteristics and a robust increase of neovascularization as evidenced by von Willebrand factor-positive angioblasts and capillaries in transplanted hearts. Thus this patch-based autologous stem cell procedure may serve as a therapeutic modality for myocardial repair.     

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.     

Targeted stem cell transplantation strategies in ALS

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that results in paralysis and ultimately death due to respiratory failure. Transplantation of neural precursor cells (NPCs) derived from the central nervous system is a promising therapeutic strategy for treatment of brain and spinal cord disorders such as ALS. ALS is a particularly challenging disease for designing relevant therapies, and presently no effective treatment exists. Despite such daunting challenges, a number of the potential benefits of NPC transplantation coincide with the neuropathological obstacles associated with ALS, including neuronal and glial replacement and non-replacement functions such as delivery of trophic support. Knowledge of the underlying disease-specific pathways involved in neurodegeneration and the contributions of different cellular subtypes to the disease go hand-in-hand with advances in NPC transplantation biology, and will aid in targeting cell-specific therapies to neurodegenerative disorders such as ALS. It is with these multiple cell targets that NPC transplantation may lend itself well to understanding and possibly slowing disease processes. A number of studies have already demonstrated the potential benefits of cell transplantation in ALS models. Lastly, practical issues such as timing and method of cell delivery, immune suppression, and the need for combinatorial approaches with non-cell based strategies must all be considered for eventual translation to the clinic.     

Allogeneic stem cell transplantation for multiple myeloma

The sensitivity of myeloma cells to high dose chemotherapy has led to the use of allogeneic hematopoietic stem cell transplantation (HSCT) as a therapeutic modality in this disease. In addition to providing more effective chemotherapy, the transplantation of allogeneic stem cells also initiates the development of an allogeneic immune response directed against residual myeloma cells. Direct evidence for a graft vs. myeloma (GVM) effect is provided by the ability of donor lymphocyte infusion (DLI) to induce significant responses in 30-50% of patients with myeloma who have relapsed after allogeneic HSCT. Nevertheless, allogeneic stem cell transplantation is also associated with a high incidence of transplant related toxicities, including regimen-related toxicities, graft vs. host disease (GVHD) and opportunistic infections. DLI has been shown to enhance immune reconstitution after allogeneic HSCT in addition to inducing a GVM response. Current efforts are directed at reducing the toxicities associated with allogeneic HSCT, identification of the target antigens of GVM and the development of new strategies to selectively enhance the immune response to myeloma cells.     

DC homeostasis in hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation is an important experimental tool and therapeutic modality. Its efficacy and toxicity are both linked to a GvH reaction that is initiated by donor T cells recognizing recipient APC, of which DC are the most potent. In most tissues recipient DC are replaced after transplantation because they turnover rapidly from BM-derived precursors. However, in a number of sites, notably the skin, recipient DC may persist and even self-renew for many months after transplantation. Understanding the homeostasis of different APC populations and how they are related to the induction of alloreactivity may help to improve the therapeutic benefit of transplantation.