Umbilical cord blood as a source of stem cells

Umbilical cord blood (UCB) is a source of the rare but precious primitive hematopoietic stem cells (HSC) and progenitor cells that can reconstitute the hematopoietic system in patients with malignant and nonmalignant disorders treated with myeloablative therapy. UCB cells possess an enhanced capacity for progenitor cell proliferation and self-renewal in vitro. UCB is usually discarded, and it exists in almost limitless supply. The blood remaining in the delivered placenta is safely and easily collected and stored. The predominant collection procedure currently practiced involves a relatively simple venipuncture, followed by gravity drainage into a standard sterile anti-coagulant-filled blood bag, using a closed system, similar to the one utilized on whole blood collection. After aliquots have been removed for routine testing, the units are cryopreserved and stored in liquid nitrogen. UCB banks are being established throughout the world and UCB units are collected for allogeneic unrelated and related HSC transplantation. In unrelated cord blood banks donated UCB units are collected and stored for allogeneic use in patients who do not have an identified HLA matched relative. UCB banks report available units to national and international donor registries. The second model of UCB banking is referred to as family banking, where UCB is stored for the benefit of the donor or their family members. After more than one decade of clinical experience, it is currently accepted that UCB transplants, related and unrelated, are equivalent to or might compare favorably with bone marrow (BM) transplants, especially in children. Initial studies of long-term survival in children with both malignant and non-malignant hematologic disorders, who were transplanted with UCB from a sibling donor, demonstrated comparable or superior survival to children who received BM transplantation. One factor that limits the use of UCB transplantation in adult patients is the relatively limited number of HSC that may be harvested from umbilical cord, resulting in a slower time to engraftment and higher transplant related mortality, mainly due to the long aplasia period after transplantation and susceptibility to viral and fungal infections. Despite prolonged periods of aplasia, the apparent reduction in the incidence and severity of graft versus host disease (GVHD) may in turn underline comparable rates of survival in some series comparing UCB to adult-donor sources. The "naive" nature of UCB lymphocytes may explain the lower incidence and severity of GVHD encountered in UCB transplantation compared to the allogeneic BM transplant setting. UCB transplantation does not seem to be associated with increased rates of disease relapse. The available data suggest that nucleated cell dose in UK unit should be the primary criterion for donor selection. In 1991, the UCB transplantation program was established at the Zagreb University Hospital Center for related transplants, and until now 4 UCB transplantations have been performed successfully. In order to speed up the engraftment rate, several strategies such as multiple UCB transplants and ex vivo expansion of HSC have been assayed. The current strategies are focused on the development of much more efficient technologies for ex vivo production of progenitor cells, but whether expansion will speed engraftment and improve outcome after UCB remains to be determined. UCB is known to contain extremely immature stem cells. Consequently, such pluripotent or, perhaps, multipotent stem cells have been proposed as elements suitable for cellular therapy and regenerative medicine. Up to date there are no conclusive data regarding these possibilities but preliminary in vitro and animal studies in the field of tissue regeneration suggest some degree of plasticity and/or transdifferentiation. UCB cells are showing their unique qualities and potential, and consequently UCB banks might dramatically increase the scope of their clinical application.     

Motivations,Experiences, and Perspectives of Bone Marrow and Peripheral Blood Stem Cell Donors: Thematic Synthesis of Qualitative Studies

Hematopoietic stem cell (HSC) transplantation using bone marrow and peripheral blood stem cells is a lifesaving treatment for patients with leukemia or other blood disorders. However, donors face the risk of physical and psychosocial complications. We aimed to synthesize qualitative studies on the experiences and perspectives of HSC donors. We searched MEDLINE, Embase, PsycINFO, CINAHL, Google Scholar, and reference lists of relevant articles to November 13, 2012. Thematic synthesis was used to analyze the findings. Thirty studies involving 1552 donors were included. The decision to donate included themes of saving life, family loyalty, building a positive identity, religious conviction, fear of invasive procedures, and social pressure and obligation. Five themes about the donation experience were identified: mental preparedness (pervasive pain, intense disappointment over recipient death, exceeding expectations, and valuing positive recipient gains), burden of responsibility (striving to be a quality donor, unresolved guilt, and exacerbated grief), feeling neglected (medical dismissiveness and family inattention), strengthened relationships (stronger family ties, establishing blood bonds), and personal sense of achievement (satisfaction and pride, personal development, hero status, and social recognition). Although HSC donation was appreciated as an opportunity to save life, some donors felt anxious and unduly compelled to donate. HSC donors became emotionally invested and felt responsible for their recipient’s outcomes and were profoundly grieved and disappointed if the transplantation was unsuccessful. To maximize donor satisfaction and mitigate the psychosocial risks for HSC donors, strategies to address the emotional challenges of anxiety, sense of coercion, guilt, and grief in donors are warranted.     

Cord blood transplant: strategy of alternative donor search

Unrelated cord blood transplantation has been used to treat patients with malignant and non-malignant hematopoietic disorders for whom an HLA-compatible hematopoietic stem cell donor is not available. The establishment of cord blood banks worldwide, the increased number of cord blood units frozen, and the shorter time to find a donor, have made it possible to use this source of hematopoietic stem cells to treat more than 2,500 patients. The Eurocord registry was established to study the clinical results of cord blood transplantation and to compare the outcomes of unrelated transplants using either cord blood or bone marrow. Briefly, we have found, in two distinct retrospective analyses of children or adults with acute leukemia given either an unrelated cord blood or bone marrow transplant, that leukemia-free survival and relapse were similar in both types of graft (with adjustment for confounding clinical factors). Cord blood recipients experienced a decreased incidence of acute graft-versus-host disease and delayed hematopoietic recovery compared to bone marrow recipients. To improve the delayed hematopoietic recovery after cord blood transplantation, certain approaches have been investigated such as ex vivo expansion of cord blood cells, double cord blood transplantation and reduced intensity conditioning regimen. We have also attempted to establish some guidelines for cord blood-donor choice based on cord blood cell dose and number of HLA disparities that have been found to be associated with hematopoietic recovery. In conclusion, an unrelated hematopoietic stem cell donor should be simultaneously searched for in cord blood banks and in bone marrow donor registries for patients lacking an HLA-identical sibling hematopoietic stem cell donor. The option of performing cord blood transplants should be based on urgency of the transplant, cord blood cell dose and number of HLA disparities.     

BMP4: its role in development of the hematopoietic system and potential as a hematopoietic growth factor

Blood formation occurs throughout the life of an individual in a process driven by hematopoietic stem cells (HSCs). The ability of bone marrow (BM) and cord blood (CB) HSC to undergo self-renewal and develop into multiple blood lineages has made these cells an important clinical resource. Transplantation with BM- and CB-derived HSCs is now used extensively for treatment of hematological disorders, malignancies, and immunodeficiencies. An understanding of the embryonic origin of HSC and the factors regulating their generation and expansion in vivo will provide important information for the manipulation of these cells ex vivo. This is critical for the further development of CB transplantation, the potential of which is limited by small numbers of HSC in the donor population. Although the origins of HSCs have become clearer and progress has been made in identifying genes that are critical for the formation and maintenance of HSCs, less is known about the signals that commit specific populations of mesodermal precursors to hematopoietic cell fate. Critical signals acting on these precursor cells are likely to be derived from visceral endoderm in yolk sac and from underlying stroma in the aorta-gonad-mesonephros region. Here we summarize briefly the origin of yolk sac and embryonic HSCs before detailing evidence that bone morphogenic protein-4 (BMP4) has a crucial role in Xenopus and mammalian HSC development. We discuss evidence that BMP4 acts as a hematopoietic growth factor and review its potential to modulate HSC in ex vivo expansion cultures from cord blood.     

Cord blood banking and transplantation

The availability of umbilical cord blood (UCB) as a source of haematopoietic stem cells (HSC) for transplantation has met an important niche in the field of HSC transplantation (HSCT) as patients unable to find a HLA-matched sibling or unrelated donor have been able to receive less well-matched UCB transplantation (UCBT) with equivalent outcomes. This has led to significant growth in this field resulting in more than 20 000 unrelated donor UCBTs performed to date with about 3000 more performed annually. Growth of UCBT has been further supported by the proliferation of public cord blood banks throughout the world which store UCB at no cost to the donor, making these available for patients all round the world through global search registries like the US National Marrow Donor Program (NMDP), NetCord and the Bone Marrow Donors Worldwide (BMDW). International organizations like the World Marrow Donor Association have also helped to steer these efforts through the formulation and distribution of guidelines and protocols for these cord blood banks and bone marrow registries. The US Food and Drug Administration (FDA) has also stepped in to regulate publicly banked UCB as an Investigational New Drug (IND). The key limiting factor in UCBT is in the limited number of cells for transplantation (about 10-fold less than donated bone marrow) resulting in delayed engraftment and even non-engraftment, particularly for adult patients for whom UCB cell doses may be insufficient relative to the patient’s body size. Efforts to overcome this barrier include the use of concurrent infusion of two differing cord blood units in order to raise the cumulative cell dose. Interestingly, this does not lead to mutual rejection of the CBUs, but appears to result in an additive effect on enhancing engraftment. Other efforts to overcome cell dose constraints of cord blood include direct bone marrow injection, use of homing molecules and ex vivo cord blood expansion. Cell dose is also an important consideration for cord blood banking as donated UCB that is collected with cell count <800 million nucleated cells has very low chance of utilization by many transplant centres which demand the best cell doses for their patients. As such, not all UCB collected is banked, although many of the low volume cords can still be reassigned to research. Strategies to increase the number of cells collected from each delivery include the use of ex utero devices which apply suction, perfusion or pressure to delivered placenta and umbilical cord in order to maximize HSC collection. Devices which enhance cell recovery during cord blood processing also help to minimize cell loss. Other strategies which might influence obstetric practice are not advised. As the worldwide experience in UCBT and UCB banking grows, patient outcomes have continued to improve such that UCBT now has a firm place in the HSCT spectrum of care with even greater potential for growth in the years to come. The challenge is for these advances to stay cost-effective so that the majority of patients can still have access to them.     

Hematopoietic Stem Cell Transplantation and Hematopoietic Stem Cell Gene Therapy in X‐Linked Adrenoleukodystrophy

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only therapeutic approach that can arrest cerebral demyelination of X‐linked adrenoleukodystrophy (ALD) in boys and results in long‐term in a good quality of life, provided the procedure is performed at an early stage of disease. Similar benefits of allogeneic HSCT have been demonstrated in adults with cerebral ALD. However, it is not yet known whether allogeneic HSCT can prevent or rescue adrenomyeloneuropathy. Allogeneic HSCT remains associated with significant morbidity and mortality risks, particularly in adults, and not all ALD patients have donors despite the availability of cord blood. The absence of biological markers that can predict the evolutivity of cerebral disease is a major limitation to propose in due time allogeneic HSCT to ALD patients. Recently, HSC gene therapy using lentiviral vector was shown to have comparable efficacy than allogeneic HSCT in two boys with cerebral ALD who had no Human‐leukocyte‐antigen (HLA)‐matched donor. If these results are confirmed in an extended series of patients, HSC gene therapy may become the first therapeutic option for all ALD male patients who develop cerebral demyelination.     

CD26 inhibition on CD34+ or lineage- human umbilical cord blood donor hematopoietic stem cells/hematopoietic progenitor cells improves long-term engraftment into NOD/SCID/Beta2null immunodeficient mice

Given the tremendous need for and potential of umbilical cord blood (CB) to be utilized as a donor source for hematopoietic stem cell (HSC) transplantation in adults, there is a strong push to overcome the constraints created by the limited volumes and subsequent limited HSC and hematopoietic progenitor cell (HPC) numbers available for HSC transplantation from a single collection. We have previously described the use of CD26 inhibitor treatment of donor cells as a method to increase the transplant efficiency of mouse HSCs and HPCs into a mouse recipient. To study the use of CD26 inhibitors as a method of improving the transplantation of human CB HSCs and HPCs, we utilized the nonobese diabetic/severe combined immunodeficient/beta 2 microglobulin null (NOD/SCID/B2m(null)) immunodeficient mouse model of HSC transplantation. We report here significant improvements in the engraftment of long-term repopulating cells following the treatment of either CD34(+) or lineage negative (lin()) donor CB with the CD26 inhibitor, Diprotin A, prior to transplant. These results establish a basis on which to propose the use of CD26 inhibitor treatment of donor CB units prior to transplantation for the purpose of improving transplant efficiency and subsequently patient outcome.     

Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide for Primary Immunodeficiencies and Inherited Disorders in Children

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for some inherited disorders, including selected primary immunodeficiencies (PIDs). In the absence of a well-matched donor, HSCT from a haploidentical family donor (HIFD) may be considered. In adult recipients high-dose post-transplant cyclophosphamide (PTCY) is increasingly used to mitigate the risks of graft failure and graft-versus-host disease (GVHD). However, data on the use of PTCY in children (and especially those with inherited disorders) are scarce. We reviewed the outcomes of 27 children transplanted with an HIFD and PTCY for a PID (n = 22) or osteopetrosis (n = 5) in a single center. The median age was 1.5 years (range, .2 to 17). HSCT with PTCY was a primary procedure (n = 21) or a rescue procedure after graft failure (n = 6). The conditioning regimen was myeloablative in most primary HSCTs and nonmyeloablative in rescue procedures. After a median follow-up of 25.6 months, 24 of 27 patients had engrafted. Twenty-one patients are alive and have been cured of the underlying disease. The 2-year overall survival rate was 77.7%. The cumulative incidences of acute GVHD grade ≥ II, chronic GVHD, and autoimmune disease were 45.8%, 24.2%, and 29.6%, respectively. There were 2 cases of grade III acute GVHD and no extensive cGVHD. The cumulative incidences of blood viral replication and life-threatening viral events were 58% and 15.6%, respectively. There was evidence of early T cell immune reconstitution. In the absence of an HLA-identical donor, HIFD HSCT with PTCY is a viable option for patients with life-threatening inherited disorders.     

A novel method of bone marrow transplantation (BMT) for intractable autoimmune diseases

We have previously proposed that autoimmune diseases are hemopoietic stem cell (HSC) disorders. In this review article, we provide evidence that most age-associated diseases such as osteoporosis are mesenchymal stem cell (MSC) disorders and, based on this evidence, we propose a new concept of "stem cell disorders (SCDs)", including HSC and MSC disorders. To treat SCDs, we have recently developed a new strategy (intra-bone marrow-bone marrow transplantation: IBM-BMT) for replacing the abnormal stem cells of recipients with donor-derived normal stem cells (both HSCs and MSCs). We here show that this strategy not only can be used to treat SCDs but is also applicable to organ transplantation, since IBM-BMT can induce tolerance (full chimerism) without the need for immunosuppressants even when radiation doses as the conditioning regimen of BMT are reduced to less than 5.0 Gy x 2, which is equivalent to one shot of 8 Gy (a sublethal dose). We believe that this strategy heralds a revolution in the field of transplantation (BMT and organ transplantation) and regeneration therapy.     

Update on gene therapy for immunodeficiencies

Primary immune deficiencies (PID) are due to blood cell defects and can be treated with transplantation of normal hematopoietic stem cells (HSC) from another person (allogeneic). Gene therapy in which a patient's autologous HSC are genetically corrected represents an alternative treatment for patients with PID, which could avoid the immunologic risks of allogeneic HSCT and confer similar benefits. Recent clinical trials using gene therapy have led to immune restoration in patients with X-linked severe combined immune deficiency (XSCID), adenosine deaminase (ADA)-deficient SCID and chronic granulomatous disease (CGD). However, severe complications arose in several of the patients in whom the integrated retroviral vectors led to leukoproliferative disorders. New approaches using safer integrating vectors or direct correction of the defective gene underlying the PID are being developed and may lead to safer and effective gene therapy for PID.     

The niche as a target for hematopoietic manipulation and regeneration

Hematopoietic stem cells (HSCs), rare primitive cells capable of reconstituting all blood cell lineages, are the only stem cells currently routinely used for therapeutic purposes. Clinical experience has shown that HSC number is an important limiting factor in treatment success. Strategies to expand HSCs are of great clinical appeal, as they would improve therapeutic use of these cells in stem cell transplantation and in conditions of bone marrow failure. The microenvironment in which HSCs reside, known as the niche, has long been considered a critical regulator of HSCs. Data accumulated over the past decade strongly confirm the importance of the niche in HSC behavior. A number of niche components as well as signaling pathways, such as Notch, have been implicated in the interaction of the microenvironment with HSCs and continue to be genetically evaluated in the hope of defining the critical elements that are required and which, if modified, can initiate HSC behaviors. In this review, we highlight the known characteristics of HSCs, challenges in their expansion, the niche phenomenon, and explain why niche stimulated HSC expansion is of utmost interest in the field, while beginning to bring to the fore potential caveats of niche manipulation. Lastly, the potential pitfalls of avoiding malignancy and controlling self-renewal versus differentiation will be briefly reviewed.     

Non-myeloablative conditioning for hemopoietic stem cell transplantation--does it work?

Allogeneic bone marrow or peripheral blood stem cell transplantation traditionally uses myeloablative regimen for conditioning to enable grafting of donor's stem cells. Animal experiments have shown that a milder non-myeloablative conditioning regimen does allow engraftment to occur. Nonmyeloablative conditioning regimens are low-intensity immunosuppressive treatment given to the recipient before infusion of donor's stem cells. It was reported to have decreased immediate procedural mortality, in particular those secondary to acute graft versus host reaction. However, it did give rise to higher risks of graft rejection, tumour tolerance and disease progression. Fortunately, appropriately administered donor lymphocyte infusion has been shown to establish full donor chimerism (complete donor stem cell grafting in the recipient's bone marrow) and potentiate antitumour effect (graft versus tumour reaction). The reduction of immediate transplant mortality allows the procedure to be carried out in older age groups, patients with concomitant diseases that otherwise would have made the patients unfit for the procedure, patients with non-malignant disorders such as congenital immune deficiencies, autoimmune disorders or thalassaemia majors. The regimen also allows transplantation of genetically manipulated haemopoietic stem cells (gene thrapy) to be carried out more readily in the immediate future. Lastly, the regimen may serve as a platform for immunotherapy using specific T cell clones for anti-tumour therapy with or without the knowledge of known tumour antigen.     

Frequency and targeted detection of HLA-DPB1 T cell epitope disparities relevant in unrelated hematopoietic stem cell transplantation.

The majority of unrelated donor (UD) hematopoietic stem cell (HSC) transplants are performed across HLA-DP mismatches, which, if involving disparity in a host-versus-graft (HVG) direction for an alloreactive T cell epitope (TCE), have been shown by our group to be associated with poor clinical outcome in 2 cohorts of patients transplanted for hematopoietic malignancies and beta-thalassemia, respectively. Using site-directed mutagenesis of DPB1*0901, we show here that the TCE is abrogated by the presence of amino acids LFQG in positions 8-11 of the DP beta-chain. Based on this and on alloreactive T cell responsiveness, we have determined the presence or absence of the TCE for 72 DPB1 alleles reported in the ethnic groups representative of the worldwide UD registries, and predict that 67%-87% (mean 77%) of UD recipient pairs will not present a DPB1 TCE disparity in the HVG direction. We developed and validated in 112 healthy Italian blood donors an innovative approach of DPB1 epitope-specific typing (EST), based on 2 PCR reactions. Our data show that DPB1 TCE disparities may hamper the clinical success of a considerable number of transplants when DPB1 matching is not included into the donor selection criteria, and that a donor without DPB1 TCE disparities in the HVG direction can be found for the majority of patients. Moreover, the study describes the first protocol of targeted epitope-specific DPB1 donor-recipient matching for unrelated HSC transplantation. This protocol will facilitate large-scale retrospective clinical studies warranted to more precisely determine the clinical relevance of DPB1 TCE disparities in different transplant conditions.     

Bone marrow tissue engineering

The creation of mixed hematopoietic chimerism has become an important clinical strategy for tolerance induction for cellular and organ transplantation, and for the treatment of numerous hematopoietic diseases. Clinical success has been limited however, by host immune response and by competition from host hematopoiesis. Recent data suggests that limited donor stem cell engraftment after minimally myeloablative hematopoietic stem cell (HSC) transplantation may in part be due to MHC associated microenvironmental mismatch resulting in a competitive disadvantage for donor HSC. A strategy to overcome this barrier to stable mixed hematopoietic chimerism would involve concurrent transplantation of a donor bone marrow microenvironment. To test this possibility, we set out to develop a method to tissue engineer a bone marrow microenvironment. One to two murine femurs were mechanically crushed to a fine suspension and were combined in vitro with various delivery vehicles. These constructs were transplanted into syngeneic animals in locations that are known to support transplantation of other tissues. Although bone formation was observed with several conditions, bone marrow formation was noted only within the small bowel mesentery when type I collagen was used as the delivery vehicle. No bone marrow formed when the vehicle was changed to polyglycolic acid or type IV collagen. We have demonstrated that the small bowel mesentery can support bone marrow formation under specific in vivo conditions. Future work will focus on strategies for transplantation of an engineered donor bone marrow environment to facilitate creation of allogeneic mixed hematopoietic chimerism.     

A tale of two SCIDs

Hematopoietic stem cell (HSC) transplantation may be curative for severe combined immunodeficiency (SCID). However, for a majority of infants with SCID a suitable donor is not available, and even with a matched donor, allogeneic HSC transplantation itself carries potential complications such as graft-versus-host disease as well as side effects from myelosuppressive chemotherapy. In the past decade, substantial advances have been made in the transplantation of gene-modified autologous HSCs, especially for two forms of SCID: X-linked SCID (SCID-X1) and adenosine deaminase (ADA)-deficient SCID. Two new reports in this issue of Science Translational Medicine add to the accumulating findings from gene therapy trials in Italy, France, and the United States that show clinical benefits of this alternative treatment.     

Donor selection for unrelated cord blood transplants

The number of unrelated cord blood transplants is increasing, with more than 8000 patients reported worldwide. Criteria of donor choice have been identified. Cell dose measured by number of nucleated cells is the most important factor, thus increases in cell dose can partially overcome the presence of HLA incompatibilities. Overall, increasing the number of HLA incompatibilities is associated with non-engraftment, but it also decreases the risk of relapse in patients with malignant disease, resulting in an absence of effect of HLA incompatibilities on event-free survival (survival without relapse or complications related to the transplant). However, in patients with non-malignant disorders, increasing the number of HLA incompatibilities decreases the overall survival. These results show that criteria of donor choice based on number of infused cells, number of HLA incompatibilities and diagnosis improve outcomes of unrelated cord blood transplants. Currently, owing to the possibility of using a non HLA identical donor, most patients can find a donor, increasing the need for the development of the inventory of cord blood banks. Methods of improving engraftment are currently under investigation.     

Biomaterial implants mediate autologous stem cell recruitment in mice

Autologous stem cells, recognized as the best cells for stem cell therapy, are associated with difficult extraction procedures which often lead to more traumas for the patients and time-consuming laboratory work, which delays their subsequent application. To combat such challenges, it was recently uncovered that, shortly after biomaterial implantation, following the recruitment of inflammatory cells, substantial numbers of mesenchymal stem cells (MSC) and hematopoietic stem cells (HSC) were recruited to the implantation sites. These multipotent MSC could be differentiated into various lineages in vitro. Inflammatory signals may be responsible for the gathering of stem cells, since there is a good relationship between biomaterial-mediated inflammatory responses and stem cell accumulation in vivo. In addition, the treatment with the anti-inflammatory drug dexamethasone substantially reduced the recruitment of both MSC and HSC. The results from this work support that such strategies could be further developed towards localized recruitment and differentiation of progenitor cells. This may permit the future development of autologous stem cell therapies without the need for tedious cell isolation, culture and transplantation.     

Some Dynamic Aspects of Hematopoietic Stem Cells

Hematopoiesis is the process responsible for maintaining the number of circulating blood cells that are undergoing continuous turnover. At the root of this process are the hematopoietic stem cells (HSC). In the following we discuss various dynamic aspects of HSC behavior ranging from the number of active stem cells, their expansion during ontogeny and the importance of stochastic effects on their behavior. We show how mathematical modeling of HSC behavior can provide important insights on these cells and clarify the implications of these dynamical aspects on healthy and sick individuals, as such providing rational explanations for relevant clinical observations on disorders that originate in this group of cells.     

Human T‐lymphotropic virus type 1 infection and solid organ transplantation

HTLV infection appears to be more common among renal transplant candidates than in the related general population. HTLV‐1‐associated diseases may occur in carriers who are transplanted but there is insufficient evidence to confirm whether these occur more frequently as a result of the associated immunosuppression. Consequently, pre‐existing HTLV‐1 infection should not be considered a contra‐indication to transplantation. The risk of transmission of HTLV‐1 through solid organ transplantation from a confirmed infected donor is unknown. There are anecdotes of multiple infections from a single donor. Biologically due to the significant volume of blood and the lack of storage, transmission would be expected to be higher than following blood transfusion. The rate of subsequent disease is unknown, but there are now 11 reports of HAM and 2 of ATL occurring within 4 years of transplantation associated infection. There are insufficient data to know whether the time from infection to onset of disease and the rate of progression differ from transmission through other routes, but early onset and rapid progression is a concern. Responses to enhanced immunosuppression for the treatment of HAM are variable. The risk of HTLV‐1 associated disease in exchange for a life‐saving major organ transplantation from an infected donor might be considered worth taking by some HTLV‐1 uninfected patients. Peri‐transplantation antiretroviral prophylaxis with zidovudine and raltegravir is biologically sound but therapeutically unproven. The risks related to HTLV‐1 infection appear to preclude the use of any other tissue. All transplant donors should be screened for HTLV‐1 infection regardless of perceived risk.     

Neuropathology of Immunosuppression

Traditionally, the brain has been considered an "immunologically privileged" organ. Under normal conditions, the blood-brain barrier (BBB) is highly effective in preventing both cellular and humoral constituents of the blood from entering the brain parenchyma. In certain pathological conditions, such as viral infections and demyelinating disorders, the BBB may become altered, activated T cells and monocytes may gain access to the brain parenchyma, and microglia may assume the functions of antigen-presenting cells and macrophages. Naturally-occurring or clinically-induced immunosuppression may dramatically alter various cellular and/or humoral aspects of the immune system. Consequently, the brain may become susceptible to disorders that would otherwise be excluded or may develop more severe manifestations of diseases, such as certain infections. This review considers the neuropathologic aspects of various conditions that may be encountered in the setting of both acquired and inherited immunosuppression. The major categories include infectious, neoplastic, vascular, and metabolic disorders. The review also briefly addresses the neuropathology of complications of chemotherapeutic agents, radiotherapy, and organ transplantation inasmuch as they often occur in the clinical setting of acquired immunosuppression.