Prophylactic rituximab after allogeneic transplantation decreases B-cell alloimmunity with low chronic GVHD incidence
2012; 119 (25): 6145-6154
Co-transplantation of pure blood stem cells with antigen-specific but not bulk T cells augments functional immunity
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2012; 109 (15): 5820-5825
B cells are involved in the pathogenesis of chronic GVHD (cGVHD). We hypothesized that prophylactic anti-B-cell therapy delivered 2 months after transplantation would decrease allogeneic donor B-cell immunity and possibly the incidence of cGVHD. Therefore, in the present study, patients with high-risk chronic lymphocytic leukemia (n = 22) and mantle-cell lymphoma (n = 13) received a total lymphoid irradiation of 80 cGy for 10 days and antithymocyte globulin 1.5 mg/kg/d for 5 days. Rituximab (375 mg/m(2)) was infused weekly on days 56, 63, 70, and 77 after transplantation. The incidence of acute GVHD was 6%. The cumulative incidence of cGVHD was 20%. Nonrelapse mortality was 3%. Rituximab treatment after allogeneic transplantation significantly reduced B-cell allogeneic immunity, with complete prevention of alloreactive H-Y Ab development in male patients with female donors (P = .01). Overall survival and freedom from progression at 4 years for chronic lymphocytic leukemia patients were 73% and 47%, respectively; for mantle-cell lymphoma patients, they were 69% and 53%, respectively.
View details for DOI 10.1182/blood-2011-12-395970
View details for Web of Science ID 000307398700030
View details for PubMedID 22563089
Sirolimus and mycophenolate mofetil as GVHD prophylaxis in myeloablative, matched-related donor hematopoietic cell transplantation
BONE MARROW TRANSPLANTATION
2012; 47 (4): 581-588
Impaired immunity is a fundamental obstacle to successful allogeneic hematopoietic cell transplantation. Mature graft T cells are thought to provide protection from infections early after transplantation, but can cause life-threatening graft-vs.-host disease. Human CMV is a major pathogen after transplantation. We studied reactivity against the mouse homologue, murine CMV (MCMV), in lethally irradiated mice given allogeneic purified hematopoietic stem cells (HSCs) or HSCs supplemented with T cells or T-cell subsets. Unexpectedly, recipients of purified HSCs mounted superior antiviral responses compared with recipients of HSC plus unselected bulk T cells. Furthermore, supplementation of purified HSC grafts with CD8(+) memory or MCMV-specific T cells resulted in enhanced antiviral reactivity. Posttransplantation lymphopenia promoted massive expansion of MCMV-specific T cells when no competing donor T cells were present. In recipients of pure HSCs, naive and memory T cells and innate lymphoid cell populations developed. In contrast, the lymphoid pool in recipients of bulk T cells was dominated by effector memory cells. These studies show that pure HSC transplantations allow superior protective immunity against a viral pathogen compared with unselected mature T cells. This reductionist transplant model reveals the impact of graft composition on regeneration of host, newly generated, and mature transferred T cells, and underscores the deleterious effects of bulk donor T cells. Our findings lead us to conclude that grafts composed of purified HSCs provide an optimal platform for in vivo expansion of selected antigen-specific cells while allowing the reconstitution of a naive T-cell pool.
View details for DOI 10.1073/pnas.1120237109
View details for Web of Science ID 000302533500055
View details for PubMedID 22440752
Early CMV Viremia Is Associated with Impaired Viral Control following Nonmyeloablative Hematopoietic Cell Transplantation with a Total Lymphoid Irradiation and Antithymocyte Globulin Preparative Regimen
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
2011; 17 (5): 693-702
We investigated sirolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis in patients with advanced hematological malignancies receiving myeloablative hematopoietic cell transplantation (HCT) from HLA-identical sibling donors. On the basis of pre-study stopping rules, the trial was closed to accrual after enrollment of 11 adult patients. In all, 7 of the 11 patients received BU-containing preparative regimens. Sirolimus was discontinued in three patients because of the toxicity-related events of severe sinusoidal obstructive syndrome, portal vein thrombosis, altered mental status and in one patient because of the risk of poor wound healing. In all, 6 of the 11 patients developed grade II-IV acute GVHD (AGVHD) a median of 15.5 days post HCT. Two of three patients with grade IV AGVHD had sirolimus discontinued by 9 days post HCT. All patients responded to AGVHD therapy without GVHD-related deaths. There were two non-relapse- and two relapse-related deaths. At a median follow-up of 38 months (2-47 months), 7 of 11 patients were alive without disease. MMF and sirolimus GVHD prophylaxis did not reduce the risk of AGVHD, however, there were no GVHD-related deaths. The severe toxicities in the patients receiving the BU-containing preparative regimens limited the continued use of sirolimus and MMF for the prevention of AGVHD.
View details for DOI 10.1038/bmt.2011.104
View details for Web of Science ID 000302576700018
View details for PubMedID 21552302
Treatment of Acyclovir-Resistant Herpes Simplex Virus with Continuous Infusion of High-Dose Acyclovir in Hematopoietic Cell Transplant Patients
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
2011; 17 (2): 259-264
The reconstitution of immune function after hematopoietic cell transplant (HCT) plays an important role in the control of viral infections. Both donor and recipient cytomegalovirus (CMV) serostatus has been shown to contribute to effective immune function; however, the influence of a nonmyeloablative preparative (NMA) regimen using total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) on antiviral immune reconstitution has not yet been described. In 117 recipients of NMA HCT patients following ATG and TLI, not unexpectedly, CMV viremia was seen in approximately 60% of the seropositive patients regardless of donor serostatus, and recipient seropositivity significantly increased the odds of CMV viremia after transplant in a multivariate analysis. The administration of ATG and TLI resulted in a strikingly earlier viremia in the posttransplant period when compared to the previously reported timing of viremia following myeloablative preparative regimens, especially for transplant recipients who were seropositive for CMV with seronegative donors. Furthermore, early viremia in the setting of a CMV naïve donor was associated with a delay in functional antiviral control. These observations demonstrate the dynamic nature of immunity in relation to CMV antigen exposure in the complex environment resulting from NMA conditions where both donor and residual recipient immune response affect viral control.
View details for DOI 10.1016/j.bbmt.2010.08.010
View details for Web of Science ID 000290061500012
View details for PubMedID 20736077
Long-term outcomes in patients with high-risk myeloid malignancies following matched related donor hematopoietic cell transplantation with myeloablative conditioning of BU, etoposide and CY
BONE MARROW TRANSPLANTATION
2011; 46 (2): 192-199
Infection because of herpes simplex virus (HSV) that is resistant to acyclovir (ACV) poses treatment challenges in hematopoietic cell transplant (HCT) patients. We present a series of patients with ACV-resistant HSV following HCT who were successfully treated with continuous infusion high-dose ACV after failing standard treatment regimens for ACV-resistant HSV.
View details for DOI 10.1016/j.bbmt.2010.06.020
View details for Web of Science ID 000287350400010
View details for PubMedID 20615475
Combined Effects of Interleukin-7 and Stem Cell Factor Administration on Lymphopoiesis after Murine Bone Marrow Transplantation
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
2011; 17 (1): 48-60
Patients with high-risk or advanced myeloid malignancies have limited effective treatment options. These include high-dose therapy followed by allogeneic hematopoietic cell transplantation (HCT). We report a single-institution, long-term follow-up of 96 patients, median age 50 (range, 20-60) years, who received HLA-matched related HCT between 1992 and 2007. All patients were treated with a uniform preparatory regimen intended to enhance the widely used regimen of BU and CY that included: BU 16.0?mg/kg (days -8 to -5), etoposide 60?mg/kg (day -4), CY 60?mg/kg (day -2) with GVHD prophylaxis of CsA or FK506 and prednisone. Disease status at transplantation was high-risk AML (n=41), CML in second chronic phase or blast crisis (n=8), myelofibrosis and myeloproliferative disorders (n=8), and myelodysplasia (n=39). Thirty-six percent (n=35) of patients received BM whereas 64% (n=61) received G-CSF-mobilized PBPC. With a median follow-up of 5.6 years (range, 1.6-14.6 years) actuarial 5-year OS was 32% (95% CI 22-42) and 5-year EFS was 31% (95% CI 21-41). Relapse rate was 24% (95% CI 15-33) at 2 and 5 years. Nonrelapse mortality was 29% (95% CI 20-38) at day 100 and 38% (95% CI 29-47) at 1 year. Cumulative incidence of acute (grade II-IV) and extensive chronic GVHD was 27% (95% CI 18-36) and 29% (95% CI 18-40), respectively. There was no statistically significant difference in OS (31 vs 32%, P=0.89) or relapse rates (17 vs 28%, P=0.22) for recipients of BM vs PBPC, respectively. These results confirm that patients with high-risk or advanced myeloid malignancies can achieve long-term survival following myeloablative allogeneic HCT with aggressive conditioning.
View details for DOI 10.1038/bmt.2010.114
View details for Web of Science ID 000287190700004
View details for PubMedID 20498648
A 39-Year-Old Woman With Lupus, Myositis, and a Recalcitrant Vasculopathy
ARTHRITIS CARE & RESEARCH
2010; 62 (9): 1351-1356
Utility of Influenza Vaccination for Oncology Patients
JOURNAL OF CLINICAL ONCOLOGY
2010; 28 (14): 2481-2490
The decreased ability of the thymus to generate T cells after bone marrow transplantation (BMT) is a clinically significant problem. Interleukin (IL)-7 and stem cell factor (SCF) induce proliferation, differentiation, and survival of thymocytes. Although previous studies have shown that administration of recombinant human IL-7 (rhIL-7) after murine and human BMT improves thymopoiesis and immune function, whether administration of SCF exerts similar effects is unclear. To evaluate independent or combinatorial effects of IL-7 and SCF in post-BMT thymopoiesis, bone marrow (BM)-derived mesenchymal stem cells transduced ex vivo with the rhIL-7 or murine SCF (mSCF) genes were cotransplanted with T cell-depleted BM cells into lethally irradiated mice. Although rhIL-7 and mSCF each improved immune reconstitution, the combination treatment had a significantly greater effect than either cytokine alone. Moreover, the combination treatment significantly increased donor-derived common lymphoid progenitors (CLPs) in BM, suggesting that transplanted CLPs expand more rapidly in response to IL-7 and SCF and may promote immune reconstitution. Our findings demonstrate that IL-7 and SCF might be therapeutically useful for enhancing de novo T cell development. Furthermore, combination therapy may allow the administration of lower doses of IL-7, thereby decreasing the likelihood of IL-7-mediated expansion of mature T cells.
View details for DOI 10.1016/j.bbmt.2010.07.027
View details for Web of Science ID 000286173400003
View details for PubMedID 20713165
Comparison of polymerase chain reaction of polymorphonuclear leukocytes and plasma identifies patients who control cytomegalovirus infection after hematopoietic cell transplantation
CLINICAL INFECTIOUS DISEASES
2008; 47 (4): 535-539
Every fall and winter, patients with cancer and their families ask oncologists whether they should be vaccinated for influenza. This season, with escalating concerns regarding the novel H1N1 influenza virus and its recently approved vaccine, this question has become more frequent and increasingly urgent. The purpose of this article is to review evidence related to the ability of patients with cancer to mount protective immunological responses to influenza vaccination. The literature on immunogenicity in pediatric and adult patients, those with solid tumors and hematologic malignancies, untreated and actively treated patients, and patients receiving biologic agents is summarized and reviewed. In addition, we report on potential strategies to improve the efficacy of influenza vaccination in patients with cancer, such as the timing of vaccination, use of more than a one-shot series, increasing the antigen dose, and the use of adjuvant therapies. We conclude that there is evidence that patients with cancer receiving chemotherapy are able to respond to influenza vaccination, and because this intervention is safe, inexpensive, and widely available, vaccination for seasonal influenza and the novel H1N1 strain is indicated.
View details for DOI 10.1200/JCO.2009.26.6908
View details for Web of Science ID 000277389600024
View details for PubMedID 20385981
Safety and immunogenicity of a bivalent cytomegalovirus DNA vaccine in healthy adult subjects
JOURNAL OF INFECTIOUS DISEASES
2008; 197 (12): 1634-1642
By use of an automated polymerase chain reaction test of plasma and a qualitative polymerase chain reaction assay on polymorphonuclear leukocytes, we identified a subgroup of hematopoietic cell transplant recipients who were able to control cytomegalovirus infection early after hematopoietic cell transplantation without antiviral therapy. Thirty-one percent of patients had cytomegalovirus DNA detected by qualitative polymerase chain reaction assay but had no cytomegalovirus DNA detected by the automated test; this group maintained a lower peak cytomegalovirus load, compared with the group of patients who had cytomegalovirus DNA detected by both tests (P = .03), suggesting a greater degree of functional immune reconstitution.
View details for DOI 10.1086/590151
View details for Web of Science ID 000257755700020
View details for PubMedID 18611158
The impact of regulatory T cells on T-cell immunity following hematopoietic cell transplantation
2008; 111 (2): 945-953
VCL-CB01, a candidate cytomegalovirus (CMV) DNA vaccine that contains plasmids encoding CMV phosphoprotein 65 (pp65) and glycoprotein B (gB) to induce cellular and humoral immune responses and that is formulated with poloxamer CRL1005 and benzalkonium chloride to enhance immune responses, was evaluated in a phase 1 clinical trial.VCL-CB01 was evaluated in 44 healthy adult subjects (22 CMV seronegative and 22 CMV seropositive) 18-43 years old. Thirty-two subjects received 1- or 5-mg doses of vaccine on a 0-, 2-, and 8-week schedule, and 12 subjects received 5-mg doses of vaccine on a 0-, 3-, 7-, and 28-day schedule.Overall, the vaccine was well tolerated, with no serious adverse events. Local reactions included mild to moderate injection site pain and tenderness, induration, and erythema. Systemic reactions included mild to moderate malaise and myalgia. All reactions resolved without sequelae. Through week 16 of the study, immunogenicity, as measured by enzyme-linked immunosorbant assay and/or ex vivo interferon (IFN)-gamma enzyme-linked immunospot assay, was documented in 45.5% of CMV-seronegative subjects and in 25.0% of CMV-seropositive subjects who received the full vaccine series, and 68.1% of CMV-seronegative subjects had memory IFN-gamma T cell responses at week 32.The safety and immunogenicity data from this trial support further evaluation of VCL-CB01.
View details for DOI 10.1086/588385
View details for Web of Science ID 000256315300002
View details for PubMedID 18444883
Cytomegalovirus MCK-2 controls mobilization and recruitment of myeloid progenitor cells to facilitate dissemination
2006; 107 (1): 30-38
Regulatory T cells (Tregs) prevent graft-versus-host disease (GvHD) by inhibiting the proliferation and function of conventional T cells (Tcons). However, the impact of Tregs on T-cell development and immunity following hematopoietic cell transplantation (HCT) is unknown. Using a murine GvHD model induced by Tcons, we demonstrate that adoptive transfer of Tregs leads to (1) abrogration of GvHD, (2) preservation of thymic and peripheral lymph node architecture, and (3) an accelerated donor lymphoid reconstitution of a diverse TCR-Vbeta repertoire. The resultant enhanced lymphoid reconstitution in Treg recipients protects them from lethal cytomegalovirus (MCMV) infection. By contrast, mice that receive Tcons alone have disrupted lymphoid organs from GvHD and remain lymphopenic with a restricted TCR-Vbeta repertoire and rapid death on MCMV challenge. Lymphocytes from previously infected Treg recipients generate secondary response specific to MCMV, indicating long-term protective immunity with transferred Tregs. Thymectomy significantly reduces survival after MCMV challenge in Treg recipients compared with euthymic controls. Our results indicate that Tregs enhance immune reconstitution by preventing GvHD-induced damage of the thymic and secondary lymphoid microenvironment. These findings provide new insights into the role of Tregs in affording protection to lymphoid stromal elements important for T-cell immunity.
View details for DOI 10.1182/blood-2007-07-103895
View details for Web of Science ID 000252458700071
View details for PubMedID 17916743
Protection against lethal Aspergillus fumigatus infection in mice by allogeneic myeloid progenitors is not major histocompatibility complex restricted
JOURNAL OF INFECTIOUS DISEASES
2005; 192 (9): 1666-1671
Murine cytomegalovirus encodes a secreted, pro-inflammatory chemokine-like protein, MCK-2, that recruits leukocytes and facilitates viral dissemination. We have shown that MCK-2-enhanced recruitment of myelomonocytic leukocytes with an immature phenotype occurs early during infection and is associated with efficient viral dissemination. Expression of MCK-2 drives the mobilization of a population of leukocytes from bone marrow that express myeloid marker Mac-1 (CD11b), intermediate levels of Gr-1 (Ly6 G/C), platelet-endothelial-cell adhesion molecule-1 (PECAM-1, CD31), together with heterogeneous levels of stem-cell antigen-1 (Sca-1, Ly-6 A /E). Recombinant MCK-2 mediates recruitment of this population even in the absence of viral infection. Recruitment of this cell population and viral dissemination via the bloodstream to salivary glands proceeds normally in mice that lack CCR2 and MCP-1 (CCL2), suggesting that recruitment of macrophages is not a requisite component of pathogenesis. Thus, a systemic impact of MCK-2 enhances the normal host response and causes a marked increase in myelomonocytic recruitment with an immature phenotype to initial sites of infection. Mobilization influences levels of virus dissemination via the bloodstream to salivary glands and is dependent on a myelomonocytic cell type other than mature macrophages.
View details for Web of Science ID 000234235200012
View details for PubMedID 16046529
Stepwise development of committed progenitors in the bone marrow that generate functional T cells in the absence of the thymus
JOURNAL OF IMMUNOLOGY
2005; 175 (7): 4363-4373
Invasive fungal infections are a leading cause of morbidity and mortality after myelotoxic chemotherapy or radiation exposure. The resulting depletion of myeloid precursors under these conditions appears to be the factor that limits approaches to accelerate immune reconstitution. In a murine model of myeloablation after radiation exposure, we demonstrated that highly purified common myeloid and granulocyte-monocyte progenitors (CMPs/GMPs) accelerated myeloid recovery and, thus, enhanced innate immunity as measured by survival after a lethal challenge with Aspergillus fumigatus. Of greatest significance was the demonstration that the protection afforded by CMPs/GMPs was not major histocompatibility complex restricted. Furthermore, the effect of CMP/GMP cellular therapy was additive with that of liposomal amphotericin B treatment. These observations greatly expand the potential donor pool and, thus, the clinical utility of CMP/GMP cellular therapy in patients with myeloid depletion.
View details for Web of Science ID 000232333000022
View details for PubMedID 16206084
Risks and outcomes of invasive fungal infections in pediatric patients undergoing allogeneic hematopoietic cell transplantation
BONE MARROW TRANSPLANTATION
2005; 36 (7): 621-629
We identified committed T cell progenitors (CTPs) in the mouse bone marrow that have not rearranged the TCRbeta gene; express a variety of genes associated with commitment to the T cell lineage, including GATA-3, T cell-specific factor-1, Cbeta, and Id2; and show a surface marker pattern (CD44+ CD25- CD24+ CD5-) that is similar to the earliest T cell progenitors in the thymus. More mature committed intermediate progenitors in the marrow have rearranged the TCR gene loci, express Valpha and Vbeta genes as well as CD3epsilon, but do not express surface TCR or CD3 receptors. CTPs, but not progenitors from the thymus, reconstituted the alphabeta T cells in the lymphoid tissues of athymic nu/nu mice. These reconstituted T cells vigorously secreted IFN-gamma after stimulation in vitro, and protected the mice against lethal infection with murine CMV. In conclusion, CTPs in wild-type bone marrow can generate functional T cells via an extrathymic pathway in athymic nu/nu mice.
View details for Web of Science ID 000232092600027
View details for PubMedID 16177077
Treatment of verruca vulgaris with topical cidofovir in an immunlocompromised patient: a case report and review of the literature
TRANSPLANT INFECTIOUS DISEASE
2005; 7 (3-4): 158-161
Invasive fungal infections (IFI) are the leading cause of infectious mortality in adult patients undergoing hematopoietic cell transplantation (HCT) after myeloablative conditioning, but the extent of this problem in the pediatric population is unclear. We retrospectively examined risk factors for IFI among 120 consecutive pediatric patients undergoing allogeneic HCT at a single center. The incidence of proven or probable IFI in pediatric patients during the first year after allogeneic HCT was 13%, comparable to the rate reported in adult patients; however, unlike IFI in adult patients, the majority of IFI in children occurred within the first month after transplantation. The primary risk factors for IFI were duration of neutropenia, age greater than 10 years, transplant for severe aplastic anemia or Fanconi anemia, and high-dose corticosteroid administration for 10 days or longer. IFI were more likely to be successfully treated (42%, 5/12 patients) in pediatric HCT recipients when compared to previous reports of adult recipients. Nonrelapse mortality was estimated at 17% (20/120 patients) after allogeneic HCT, of which 35% (seven patients) were directly attributed to IFI. Thus, IFI is a significant cause of nonrelapse mortality in children undergoing allogeneic HCT and more effective strategies are needed to prevent and treat IFI.
View details for DOI 10.1038/sj.bmt.1705113
View details for Web of Science ID 000231877200009
View details for PubMedID 16044133
Exogenous administration of immunomodulatory therapies in hematopoietic cell transplantation: an infectious diseases perspective
CURRENT OPINION IN INFECTIOUS DISEASES
2005; 18 (4): 352-358
Lesions caused by verrucus vulgaris are commonly refractory to therapy and may become large, painful, or disfiguring in immunocompromised patients. Cidofovir is a potent nucleoside analog antiviral agent shown to have in vitro and in vivo activity against a broad spectrum of DNA viruses. We report a successful use of topical cidofovir to treat verruca vulgaris lesions in a highly immunocompromised patient, who was not considered a candidate for conventional therapy.
View details for Web of Science ID 000236936200012
View details for PubMedID 16390407
The influence of the conditions of hematopoietic cell transplantation on infectious complications
CURRENT OPINION IN INFECTIOUS DISEASES
2005; 18 (4): 346-351
In contrast to the recipient of a solid organ transplantation, the immunological competence of recipients of hematopoietic cell transplantation does not correlate well with the administration of non-corticosteroid immunosuppressive agents. This apparent paradox reflects the unique and dynamic conglomeration of factors that affect immune reconstitution after hematopoietic cell transplantation. The following is the second part of a review of the recent primary literature regarding exogenous immunomodulatory influences as they pertain to infections in the setting of hematopoietic cell transplantation.The main themes of published primary research from 2004 to the present include the influence of exogenously administered immunomodulatory agents on infectious complications after hematopoietic cell transplantation.The use of immunomodulatory agents such as monoclonal antibodies directed against lymphocyte antigens in the treatment of hematopoietic malignancy has greatly expanded during the past decade. Separate trials of the potential utility of these agents, particularly in the reduction of graft-versus-host disease, in the setting of hematopoietic cell transplantation have yielded encouraging results. Given the infancy of these new approaches, it is not possible to make definitive statements regarding the relative risk of serious infection with each therapy. It is clear that a reduction in regimen-related non-infectious complications or mortality does not necessarily ensure a reduction in clinically significant infections. Improvements in early diagnostic and therapeutic options for these infections now bring us to an era of understanding pathogens such as cytomegalovirus as probes of the functional reconstitution of immunity.
View details for Web of Science ID 000230812700011
View details for PubMedID 15985834
Single infusion of myeloid progenitors reduces death from Aspergillus fumigatus following chemotherapy-induced neutropenia
2005; 105 (9): 3535-3537
The multitude of factors that influence the risk of infection after hematopoietic cell transplantation has been further complicated by the rapid evolution of this therapy in the past 5 years. The degree to which functional immune reconstitution has been achieved reflects the equilibrium reached by the immune systems of the recipient and donor in the context of host non-hematopoietic tissue. Thus immunomodulatory influences on the recipient and the transplanted graft, both before and after hematopoietic cell transplantation, have a profound influence on the incidence and severity of infection. This review of the recent literature contributes to our understanding of how the conditions of hematopoietic cell transplantation influence the timing and nature of infectious complications.The main themes of published primary research from 2004 to the present focus on non-myeloablative conditioning regimens and their effects on immune reconstitution after hematopoietic cell transplantation.A plethora of clinical trials are ongoing, focused on the outcome after conditioning regimens designed to result in less regimen-related toxicity while preserving or enhancing the graft-versus-tumor effect. Given the infancy of these new approaches, it is not possible to make definitive statements regarding the relative risk of serious infection with each therapy. It is clear that a reduction in regimen-related non-infectious complications or mortality does not necessarily ensure a reduction in clinically significant infections. Improvements in early diagnostic and therapeutic options for these infections now bring us to an era of understanding pathogens as probes of the functional reconstitution of immunity.
View details for Web of Science ID 000230812700010
View details for PubMedID 15985833
Rapamycin (sirolimus) for treatment of chronic graft-versus-host disease
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
2005; 11 (1): 47-55
Hematopoietic progenitors committed to the myeloid lineage, the common myeloid and granulocyte-monocyte progenitors (CMP/GMP), have been shown to protect against opportunistic pathogens following myeloablative radiation; however, the efficacy of this approach has not been studied in the setting of chemotherapy-induced neutropenia. In this mouse model, the infusion of CMP/GMP on the day after 5-fluorouracil (5-FU) administration (D+1) resulted in a significant increase in the number of splenic neutrophils by D+8 when compared with 5-FU-only controls (P = .02), the majority of which were CMP/GMP-derived (54%). Moreover, 19% and 28% of neutrophils in the blood and bone marrow, respectively, were CMP/GMP-derived. Survival following intranasal challenge with the fungus Aspergillus fumigatus was significantly higher in CMP/GMP-infused mice than the controls (56% and 33% respectively; P = .019). Thus, a single infusion of CMP/GMP enhances tissue neutrophil content and increases survival against a lethal challenge with A fumigatus in the setting of chemotherapy-induced neutropenia.
View details for DOI 10.1182/blood-2004-2004-07-2676
View details for Web of Science ID 000228797400029
View details for PubMedID 15576478
Fungal infections in bone marrow transplant patients
CURRENT OPINION IN INFECTIOUS DISEASES
2004; 17 (4): 347-352
We conducted a phase II trial in 19 chronic graft-versus-host disease (cGVHD) patients with rapamycin, calcineurin inhibitors, and prednisone with the goals of controlling cGVHD, reducing prednisone use, and defining the safety of this regimen. Rapamycin was begun as second-line (n = 9) or more than second-line (n = 10) therapy. With a median follow-up of 42 months, 16 patients were evaluable for response. Nine patients discontinued rapamycin because of poor compliance/patient request (n = 2) or an adverse event (n = 7), 3 of whom were not evaluable because of withdrawal at < or =1 month or noncompliance. The adverse events included serum creatinine > or =2.4 mg/dL (n = 4), hemolytic uremic syndrome (n = 2), and relapse of malignancy (n = 1). Fifteen of 16 evaluable patients had a clinical response. Five of the 16 discontinued the drug, and 1 died of relapsed leukemia. Of the 10 patients who continued rapamycin, 2 discontinued and 1 successfully tapered all systemic immunosuppression. Three of the 10 developed progressive cGVHD with tapering immunosuppression; all responded to resumption of prior medications. Four of the 10 patients required alternate therapy for persistent or progressive cGVHD while receiving rapamycin; prednisone was discontinued (n = 2) or tapered at the time of progressive disease (n = 2). Seventeen of 19 original patients were alive. One death was due to relapsed malignancy, and 1 was due to congestive heart failure. In this report of rapamycin as cGVHD therapy, there is evidence of rapamycin's efficacy. Given the significant toxicities described, investigation of altered administration of rapamycin and calcineurin inhibitors should be pursued in future cGVHD trials.
View details for DOI 10.1016/j.bbmt.2004.10.004
View details for Web of Science ID 000226450300006
View details for PubMedID 15625544
Common lymphoid progenitors rapidly engraft and protect against lethal murine cytomegalovirus infection after hematopoietic stem cell transplantation
2003; 102 (2): 421-428
Invasive fungal infections have become the leading infectious cause of death in recipients of hematopoietic cell transplantation. Several factors have led to a renaissance in the study of invasive fungal infections. The growing incidence of both commonly encountered as well as emerging pathogens and the lethality of these infections coupled with the unprecedented number of available broad-spectrum antifungal drugs has lent a renewed vigor and enthusiasm to attempts to understand the pathogenesis of these diseases and, by doing so, improve prevention, diagnosis, and treatment. The following is a review of the primary research published from 2003 to the present that is pertinent to invasive fungal infection in the setting of hematopoietic cell transplantation.The main themes of published primary research during 2003 to the present include the efficacy and tolerability of antifungal prophylaxis, epidemiologic analyses of risk factors following nonmyeloablative preparative regimens, and more-detailed analyses of nonmyeloid immune responses.Although few definitive recommendations emerged from the studies during the review period, these investigations do contribute to a greater understanding of the immunobiology of invasive fungal infection and of the utility and limitations of newer antifungal agents in the prophylaxis or treatment of invasive fungal infection.
View details for DOI 10.1097/01.qco0000136935.13662.af
View details for Web of Science ID 000223033000011
View details for PubMedID 15241080
Myeloid progenitors protect against invasive aspergillosis and Pseudomonas aeruginosa infection following hematopoietic stem cell transplantation
2002; 100 (13): 4660-4667
Lymphoid deficiency after allogeneic hematopoietic cell transplantation (HCT) results in increased susceptibility to infection; however, transplantation of mature lymphocytes frequently results in a serious complication known as graft-versus-host disease (GVHD). Here we demonstrate in mice that both congenic as well as allogeneic transplantation of low numbers of highly purified common lymphoid progenitors (CLPs)-a rare population of lymphoid-lineage-committed bone marrow cells-accelerates immune reconstitution after lethal irradiation and rescue with hematopoietic stem cells (HSCs). After congenic transplantation, 3 x 10(3) CLPs protected against murine cytomegalovirus (MCMV) infection at a level roughly equivalent to 107 unfractionated lymph node cells. In the allogeneic model of matched unrelated donor HSC transplantation, cotransplantation of 3 x 10(3) CLPs protected thymus-bearing as well as thymectomized hosts from MCMV infection and attenuated disease severity. Immunohistochemistry in combination with antibody depletion of T and natural killer (NK) cells confirmed that CLP-derived as well as residual host lymphocytes contribute to antiviral protection. Importantly, transplantation of allogeneic CLPs provided a durable antiviral immunity without inducing GVHD. These data support the potential for composing grafts with committed progenitors to reduce susceptibility to viral infection following HCT.
View details for DOI 10.1182/blood-2002-12-3834
View details for Web of Science ID 000184083500010
View details for PubMedID 12663447
Prophylactic administration of liposomal amphotericin B is superior to treatment in a murine model of invasive aspergillosis after hematopoietic cell transplantation
JOURNAL OF INFECTIOUS DISEASES
2002; 186 (1): 134-137
Myelotoxic treatments for oncologic diseases are often complicated by neutropenia, which renders patients susceptible to potentially lethal infections. In these studies of murine hematopoietic stem cell transplantation (HSCT), cotransplantation of lineage-restricted progenitors known as common myeloid progenitors (CMP) and granulocyte-monocyte progenitors (GMP) protects against death following otherwise lethal challenge with either of 2 pathogens associated with neutropenia: Aspergillus fumigatus and Pseudomonas aeruginosa. Cotransplantation of CMP/GMP resulted in a significant and rapid increase in the absolute number of myeloid cells in the spleen, most of which were derived from the donor CMP/GMP. Despite persistent peripheral neutropenia, improved survival correlated with the measurable appearance of progenitor-derived myeloid cells in the spleen. A marked reduction or elimination of tissue pathogen load was confirmed by culture and correlated with survival. Localization of infection by P aeruginosa and extent of disease was also assessed by in vivo bioluminescent imaging using a strain of P aeruginosa engineered to constitutively express a bacterial luciferase. Imaging confirmed that transplantation with a graft containing hematopoietic stem cells and CMP/GMP reduced the bacterial load as early as 18 hours after infection. These results demonstrate that enhanced reconstitution of a tissue myeloid pool offers protection against lethal challenge with serious fungal and bacterial pathogens.
View details for DOI 10.1182/blood-2002-05-1552
View details for Web of Science ID 000179759800058
View details for PubMedID 12393415
Immunity to infections following hematopoietic cell transplantation
CURRENT OPINION IN IMMUNOLOGY
2001; 13 (4): 451-457
With use of a novel model of invasive Aspergillus fumigatus, the efficacy of prophylactic versus therapeutic administration of liposomal amphotericin B (L-AmB) was tested in C57BL/6 mice. After lethal irradiation and transplantation of whole bone marrow (d 0), animals were challenged with conidia either intravenously or via nasal instillation on d +3 and divided into 3 groups: group I received 5% dextrose in water throughout the study period; group II received L-AmB, 5 mg/kg, beginning on d +4; and group III received L-AmB, 5 mg/kg on d -4, d -2, d 0, and d +2, then daily starting d +4. Groups I and II did not survive intravenous challenge, whereas group III had a 40% survival rate. After nasal instillation of conidia, the survival was 25%, 35%, and 85% for mice in groups I, II, and III, respectively. These results demonstrate that prophylactic administration of L-AmB increased early survival against lethal challenge with A. fumigatus, compared with therapy instituted after infection.
View details for Web of Science ID 000176307800022
View details for PubMedID 12089676
Reassessing the organization of the UL42-UL43 region of the human cytomegalovirus strain AD169 genome
1997; 239 (1): 169-175
Hematopoietic cell transplantation has progressed from the use of unpurified bone marrow cells or mobilized peripheral blood cells to the use of purified stem cells and progenitor cells. These kinds of transplants can be designed to provide not only hematopoietic rescue but also augmented innate and acquired immunity.
View details for Web of Science ID 000169648600010
View details for PubMedID 11498301
SELECTABLE INSERTION AND DELETION MUTAGENESIS OF THE HUMAN CYTOMEGALOVIRUS GENOME USING THE ESCHERICHIA-COLI GUANOSINE PHOSPHORIBOSYL TRANSFERASE (GPT) GENE
JOURNAL OF GENERAL VIROLOGY
1995; 76: 2151-2160
A polymorphism in the UL42-UL43 region of the human cytomegalovirus genome has been characterized by nucleotide sequence analysis, revealing a 929-bp insertion following nt 54,612 relative to the published strain AD169-UK genome sequence (M.S. Chee et al., 1990, Curr. Top. Microbiol Immunol. 154, 125-170). Although AD169-UK exhibited polymorphism in this genomic region, other CMV strains (Towne, Toledo, and AD169-ATCC) carried only the newly characterized longer form. The additional sequence altered the assignment of UL42 and UL43 open reading frames. UL42 decreased in size from 157 to 125 codons, retaining 76 of the previously reported carboxyl terminal codons, and UL43 increased in size from 187 to 423 codons, retaining 185 of the previously reported amino terminal codons. This additional sequence makes UL43 a more conserved betaherpesvirus US22 family member. Only AD169-UK exhibited restriction fragment length polymorphism in this region, suggesting that a deletion occurred during the propagation of this strain in cell culture. The additional sequence should be considered a bona fide part of the cytomegalovirus genome and the AD169 genome size should be corrected to 230,283 bp.
View details for Web of Science ID 000071139000016
View details for PubMedID 9426456
DRAMATIC INTERSTRAIN DIFFERENCES IN THE REPLICATION OF HUMAN CYTOMEGALOVIRUS IN SCID-HU MICE
JOURNAL OF INFECTIOUS DISEASES
1995; 171 (6): 1599-1603
We describe the mutagenesis of the IRSI-US5 region of the human cytomegalovirus genome, demonstrating the potential of the E. coli guanosine phosphoribosyl transferase (gpt) gene as a selectable marker for insertion and deletion mutagenesis of high passage (AD169, Towne) as well as low passage (Toledo) strains of virus. Despite evidence suggesting that the US3 gene product may play a regulatory role, disruption of this gene with a gpt insert had no effect on growth of any of these strains of virus in resting or dividing human fibroblasts, or in human thymus plus liver implants in SCID-hu mice. Transcripts of the gpt gene, under control of the herpes simplex virus thymidine kinase promoter adjacent to the US3 enhancer in the viral genome, accumulated with delayed early (beta) kinetics. Mutants with deletions in the IRS1 and US3-US5 regions were isolated by back-selection against gpt with the drug 6-thioguanine by growing virus in human Lesch-Nyhan (hypoxanthine-guanine phosphoribosyl transferase deficient) skin fibroblasts immortalized with human papillomavirus oncogenes. Thus, we demonstrate a dependable method for insertion and deletion mutagenesis that can be applied to any region of the viral genome.
View details for Web of Science ID A1995RT16600005
View details for PubMedID 7561752
The ability of a low-passage strain (Toledo) and laboratory strains (AD169 and Towne) of human cytomegalovirus to replicate in SCID-hu (thymus plus liver) mice were compared. At a time of peak replication, 14 days after inoculation, the Toledo strain grew 2-3 orders of magnitude better than any laboratory strain, a difference reflecting the number of infected thymic stromal cells in the implants. The growth property of the Toledo strain was stable through serial passage and plaque purification. The AD169-ATCC strain failed to grow at all, while an independently maintained stock of this strain obtained from the United Kingdom replicated to low levels, suggesting that divergence had occurred during propagation in different locations. This work predicts the existence of viral genetic determinant(s) for growth in tissues that are lost during propagation in culture.
View details for Web of Science ID A1995RB29800030
View details for PubMedID 7769298