Persis J Amrolia

University College London, Londinium, England, United Kingdom

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Publications (83)490.9 Total impact

  • Persis J Amrolia, Martin Pule
    Lancet. 10/2014;
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    ABSTRACT: EBV associated post-transplant lymphoma (PTLD) is a major cause of morbidity/mortality after hematopoietic stem cell (SCT) or solid organ (SOT) transplant. Adoptive immunotherapy with EBV-specific cytotoxic lymphocytes (CTLs), whilst effective in SCT, is less successful after SOT where life-long immunosuppression therapy is necessary. We have genetically engineered EBV-CTLs to render them resistant to calcineurin inhibitor FK506 through retroviral transfer of a calcineurin A mutant (CNA12). Here we examined the ability of FK506-resistant EBV-CTLs to control EBV-driven tumour progression in the presence of immunosuppression in vivo in a xenogeneic mouse model. NOD/SCID/IL2rγ(null) mice bearing human B cell lymphoma were injected with autologous CTLs transduced either with CNA12 or eGFP in the presence/absence of FK506. Adoptive transfer of autologous CNA12-CTLs induced dramatic lymphoma regression despite the presence of FK506 whereas eGFP transduced CTLs did not. CNA12-CTLs persisted longer, homed to the tumour and expanded more than eGFP-CTLs in mice treated with FK506. Mice receiving CNA12-CTLs and treated with FK506 survived significantly longer than control treated animals. Our results demonstrate that CNA12-CTL induce regression of EBV-associated tumours in vivo despite ongoing immunosuppression. Clinical application of this novel approach may enhance the efficacy of adoptive transfer of EBV-CTL in SOT patients developing PTLD without the need for reduction in immunosuppressive therapy.
    Blood 09/2014; · 9.78 Impact Factor
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    ABSTRACT: Severe combined immunodeficiency (SCID) can be cured by using allogeneic hematopoietic stem cell transplantation, and the absence of host immunity often obviates the need for preconditioning. Depending on the underlying genetic defect and when blocks in differentiation occur during lymphocyte ontogeny, infants with SCID have absent or greatly reduced numbers of functional T cells. Natural killer (NK) cell populations are usually absent in the SCID-X1 and Janus kinase 3 forms of SCID and greatly reduced in adenosine deaminase deficiency SCID but often present in other forms of the disorder. To determine if SCID phenotypes indicate host permissiveness to donor cell engraftment. A retrospective data analysis considered whether host NK cells influenced donor T-cell engraftment, immune reconstitution, and long-term outcomes in children who had undergone nonconditioned allogeneic stem cell transplantation between 1990 and 2011 in the United Kingdom. Detailed analysis of T- and B-cell immune reconstitution and donor chimerism was compared between the NK(+) (n = 24) and NK(-) (n = 53) forms of SCID. Overall, 77 children underwent transplantation, with survival of 90% in matched sibling donor/matched family donor transplants compared with 60% when alternative donors were used. Infants with NK(-)SCID were more likely to survive than NK(+) recipients (87% vs 62%, P < .01) and had high-level donor T-cell chimerism with superior long-term recovery of CD4 T-cell immunity. Notably, 33% of children with NK(+)SCID required additional transplantation procedures compared with only 8% of children with NK(-)SCID (P < .005). NK(-)SCID disorders are highly permissive for donor T-cell engraftment without preconditioning, whereas the presence of NK cells is a strong indicator that preparative conditioning is required for engraftment of T-cell precursors capable of supporting robust T-cell reconstitution.
    The Journal of allergy and clinical immunology 04/2014; · 12.05 Impact Factor
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    ABSTRACT: Background. Although CMVR is a well-recognized complication following allogeneic HSCT, standard operating procedures for ophthalmic monitoring are variable. In particular, we perceived greater risk of CMVR after pediatric HSCT for inherited immunodeficiencies, who often have pre-transplant viremia. This study was therefore performed with an objective of identifying high-risk pediatric HSCT recipients who would benefit from regular ophthalmic monitoring. Methods. During a five year study period, 56 of 304 consecutive HSCT recipients (aged 0.5 to 197 months) who developed significant CMV viremia (CMVPCR≥4000 copies/ml) were retrospectively analyzed. All HSCT recipients who developed significant CMV viremia underwent weekly (inpatients) or every other week (outpatients) retinal examination, performed by a skilled ophthalmologist. Results. Thirteen (4%) of 304 HSCT recipients developed CMVR. This amounted to 23% (13/56) of those with significant CMV viremia. Pre-transplant viremia (odds-ratio=11.3; p<0.01), acute (≥ grade 2) graft-versus-host disease (odds-ratio=8.2; p<0.02) and mismatched graft (odds-ratio=8; p<0.02) were identified as independent risk factors. Compared to other invasive CMV diseases, CMVR was more often a late-onset disease occurring at a median of 199 days post-HSCT. At diagnosis, a significantly higher CD4 count≥200/μl (p<0.03) and a lower CMV viral load (p<0.003) was observed in children with CMVR, compared to those who developed lung, gut or liver CMV disease. Conclusion. We report increased risk of CMVR in high-risk pediatric HSCT recipients. This form of CMV disease differs from other invasive CMV disease in its relationship to immune-reconstitution and viral dynamics. We have studied the relationship between these variables and suggested a risk-stratified ophthalmic screening strategy.
    Clinical Infectious Diseases 04/2014; · 9.37 Impact Factor
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    ABSTRACT: Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (PTLD) remains a major cause of morbidity and mortality after hematopoietic stem cell (HSCT) or solid organ transplant (SOT). Strategies to reconstitute immunity by adoptive transfer of EBV-specific cytotoxic T lymphocyte (CTL) therapy while highly effective in the HSCT setting where immunosuppression can be withdrawn have been less successful in the SOT setting where continued immunosuppression therapy is necessary. Additionally, the complexity and time taken to generate EBV-CTLs for adoptive transfer limit the clinical applicability. We have developed a system for the rapid generation of EBV-CTLs resistant to immunosuppression based on selection of interferon-gamma (IFN-γ) secreting EBV-CTLs and retroviral transduction with a calcineurin B mutant. With this methodology, EBV-CTLs resistant to the calcineurin inhibitor Tacrolimus (TAC) can be produced in 14 days. These CTLs show high specificity for EBV with negligible alloreactivity in both proliferation and cytotoxicity assays and are able to proliferate and secrete IFN-γ in response to antigen stimulation in the presence of therapeutic doses of TAC. This strategy will substantially facilitate clinical application of this approach for the treatment of PTLD in SOT recipients.
    American Journal of Transplantation 12/2013; 13(12):3244-3252. · 6.19 Impact Factor
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    ABSTRACT: In vivo T-cell-depletion with Thymoglobulin (ATG) might contribute to the delayed immune reconstitution observed after unrelated umbilical cord blood transplantation (UCBT). We studied the impact of early, late and no ATG on immune reconstitution and outcome. 127 Children receiving UCBT in London or Utrecht were included into 3 groups: late ATG (day -5 to 0, n=48), early ATG (day -9 to -5, n= 33) and no ATG (n=46). The no ATG group received MMF+CsA as GVHD- prophylaxis, while the ATG groups both received CSA+prednisone. Endpoints studied were survival, immune-recovery, infections and GvHD. The probability of survival was similar in all groups: 71%+/-8%(no ATG), 68%+/-9%(early ATG) and 61%+/-7%(late ATG). CD3+, CD4+ and CD4+ naïve T-cell-counts were significantly higher (p<0.001) in the no ATG group at 1,2,3,6, and 12months post-UCBT. In the no ATG group significantly less viral reactivations(p=0.021) were noted. A higher probability of severe acute GvHD(31%) was found in the no ATG group compared to 18% (p =0.018) for early ATG and 5% (p<0.001) for late ATG. This was not associated with more chronic GvHD. The findings of improved immune-reconstitution, associated with lower viral reactivations, albeit at the cost of increased rates of acute GvHD (but not cGvHD), suggest that omitting ATG may be important to prevent viral reactivations.
    Blood 11/2013; · 9.78 Impact Factor
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    ABSTRACT: Severe combined immunodeficiency (SCID) arises from different genetic defects associated with lymphocyte development and function and presents with severe infections. Allogeneic haematopoietic stem cell transplantation (HCT) is an extremely effective way of restoring immunity in these individuals. Numerous multi-centre studies have identified the factors determining successful outcome and survival for SCID has shown great improvement. Advances in understanding the genetic basis of disease also mean that we increasingly tailor transplant protocols to the specific SCID form. Wherever possible, we attempt to transplant SCID patients without the use of cytoreductive conditioning but it is clear that this is only successful for specific SCID forms and although survival is good, in specific patients there are ongoing humoral defects. We aim to use matched related and unrelated donors (including cord blood) whenever possible and have limited the use of mismatched haploidentical donors. The development of autologous haematopoietic stem cell gene therapy provides another treatment for the X-linked and adenosine deaminase (ADA) deficient forms of SCID, and we discuss how we have integrated gene therapy into our treatment strategy. These developments together with the advent of universal newborn screening for SCID should allow for a highly favourable outcome for this otherwise lethal condition.
    Blood 10/2013; · 9.78 Impact Factor
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    ABSTRACT: Defective V(D)J recombination and DNA double-strand break (DSB) repair severely impair the development of T-lymphocytes and B-lymphocytes. Most patients manifest a severe combined immunodeficiency during infancy. We report 2 siblings with combined immunodeficiency (CID) and immunodysregulation caused by compound heterozygous Artemis mutations, including an exon 1-3 deletion generating a null allele, and a missense change (p.T71P). Skin fibroblasts demonstrated normal DSB repair by gamma-H2AX analysis, supporting the predicted hypomorphic nature of the p.T71P allele. In addition to these two patients, 12 patients with Artemis-deficient CID were previously reported. All had significant morbidities including recurrent infections, autoimmunity, EBV-associated lymphoma, and carcinoma despite having hypomorphic mutants with residual Artemis expression, V(D)J recombination or DSB repair capacity. Nine patients underwent stem cell transplant and six survived, while four patients who did not receive transplant died. The progressive nature of immunodeficiency and genomic instability accounts for poor survival, and early HSCT should be considered.
    Clinical Immunology 08/2013; 149(3PB):464-474. · 3.77 Impact Factor
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    ABSTRACT: This study investigated the cognitive and psychosocial outcomes in childhood survivors of hemophagocytic lymphohistiocytosis after hematopoietic stem cell transplantation. Twenty-one children were assessed on standardized measures of cognitive and psychosocial functioning and compared with an unaffected sibling control group (n = 14). Parent and teacher reports were obtained to provide additional information. The average full-scale intelligence quotient for the patient cohort was 81 (95% CI, 72-90), which was significantly lower than both the population average of 100 (P = .001) and the average for the unaffected sibling control group (99.2, P = .002). Fifty-six percent of school-aged children were receiving additional support at school, with the majority needing high levels of support. These children also experienced significant psychosocial difficulties. Lower socioeconomic status was associated with poorer cognitive outcomes, but age at transplantation, time to transplantation, type of conditioning, and presence of mixed chimerism were not. Ten (48%) of 21 children had evidence of neurologic involvement at diagnosis, but surprisingly, this was not significantly associated with adverse neurologic outcomes, and some children who did not have any apparent neurologic involvement at diagnosis had severe learning difficulties at follow-up. In summary, childhood survivors of hemophagocytic lymphohistiocytosis are at risk of long-term cognitive and psychosocial difficulties. Prospective and systematic long-term follow-up of these patients is essential for early identification and effective management of these problems.
    The Journal of allergy and clinical immunology 08/2013; · 12.05 Impact Factor
  • Blood 06/2013; 121(24):4966-8. · 9.78 Impact Factor
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    ABSTRACT: BACKGROUND: Primary central nervous system (PCNS) post-transplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplantation and is typically an Epstein-Barr virus (EBV)-induced B-cell CD20+ lymphoma. The modalities of treatment include reduction in immunosuppression, cranial radiotherapy (CRT), intravenous and intrathecal rituximab when CD20 is expressed on B-lymphocytes and PTLD cells, and chemotherapy. CASE-DIAGNOSIS/TREATMENT: We report the successful treatment of EBV-driven PCNS PTLD by reduction in immunosuppression (RI), CRT, and intravenous rituximab. Our patient was an 11-year-old boy with a living-related renal transplant for end-stage renal failure (ESRF) secondary to posterior urethral valves (PUV) and bilateral renal dysplasia (BRD) and on triple immunosuppression with prednisolone, tacrolimus, and azathioprine who had a rising EBV load, which was managed with reduction in tacrolimus dose, withdrawal of azathioprine, and introduction of mycophenolate mofetil (MMF). CONCLUSIONS: The patient presented 7 years post-transplant with a seizure and abnormal neurology secondary to polymorphous hyperplastic lesions in the brain, which responded to rituximab and CRT.
    Pediatric Nephrology 06/2013; · 2.94 Impact Factor
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    ABSTRACT: BACKGROUND: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare primary immune disorder defined by mutations in the syntaxin binding protein 2 (STXBP2) alias MUNC18-2. Despite defective immunity and a hyper-inflammatory state, clinical findings such as neurological, gastrointestinal, and bleeding disorders are present in a significant number of patients and suggest an impaired expression and function of STXBP2 in cells other than cytotoxic lymphocytes. PROCEDURE: We investigated four patients with FHL5 suffering from severe enteropathy and one of whom also had renal tubular dysfunction despite successful hematopoietic stem cell transplantation (HSCT). Gastrointestinal and renal biopsy specimens were analyzed by immunohistochemistry and electron microscopy. RESULTS: Histopathology revealed an intracytoplasmatic accumulation of PAS-positive granules and an enlarged intracytoplasmatic CD10-positive band along the apical pole of enterocytes. Electron microscopy revealed short microvilli and granules filled with electro lucent material. In addition, we described mildly dilated renal tubules and electron micrographs displayed a higher number of cytoplasmic inclusions, electrodense lysosomal and electrolucent endosomal vesicles. CONCLUSION: Mutations in STXBP2 do not only affect cytotoxic T lymphocytes but also cause changes in the intestinal and renal epithelium resulting in severe, osmotic diarrhea and renal proximal tubular dysfunction. These defects persist after successful treatment of hemophagocytic lymphohistocytosis by HSCT. Clinical manifestations in FHL5 patients despite successful HSCT may therefore be related to defective membrane trafficking in the gut and kidney. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 02/2013; · 2.35 Impact Factor
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    ABSTRACT: Immunotherapy with allodepleted donor T cells improves immunity after T cell-depleted hematopoietic stem cell transplantation. We developed a methodology for selective depletion of alloreactive T cells after activation with host antigen-presenting cells by targeting T cells up-regulating CD25 and CD71. Combined depletion of these cells yields a pool of allodepleted donor T cells with antiviral properties with minimal capacity to cause graft-versus-host disease. Mature dendritic cells were irradiated and used to stimulate donor peripheral blood mononuclear cells for 4 days. The co-culture was stained with anti-CD71-biotin followed by CliniMACS CD25 and Anti-Biotin Reagents (Miltenyi Biotec GmbH; Bergisch Gladbach, Germany) before depletion on the CliniMACS Plus (Miltenyi Biotec GmbH). Residual alloreactivity was tested by flow cytometry, a secondary mixed lymphocyte reaction and limiting dilution analysis, and specific anti-viral immunity with pentamer staining. The large-scale protocol was tested under current good manufacturing practice conditions in five donor-recipient pairs of human leukocyte antigen-matched volunteer donors. We developed a closed-system methodology using cell differentiation bags for cell culture and the COBE2991 Cell Processor (CaridianBCT, Lakewood, CO, USA). We also validated an anti-CD71-biotin generated for ex vivo clinical use. In five large-scale runs, the depleted fraction demonstrated excellent viability (99.9%), minimal residual expression of CD3/CD25 and CD3/CD71 (<0.2%) and passed tests for Mycoplasma, endotoxin, bacterial and fungal sterility. In secondary mixed lymphocyte reaction assays, the median response to host after allodepletion was 0%, whereas responses to third-party peripheral blood mononuclear cells were preserved (median, 105%; range 37%-350%). Limiting dilution analysis assays also demonstrated a reduction in response to host (median, -1.11 log) with preservation of third-party responses, and testing with human leukocyte antigen-restricted pentamers showed that populations of Epstein-Barr virus-specific and cytomegalovirus-specific CD8(+) T cells were retained after depletion. We optimized a protocol for the combined immunomagnetic depletion of alloreactive CD25/CD71 T cells under current good manufacturing practice conditions and tested the efficacy in five donor-recipient pairs.
    Cytotherapy 01/2013; 15(1):109-21. · 3.06 Impact Factor
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    ABSTRACT: We report two children who developed severe, fatal pulmonary hypertension (PHT) after mismatched unrelated donor cord blood transplantation using reduced intensity conditioning for HLH. PHT was diagnosed on post mortem lung biopsies with no evidence of HLH, pulmonary veno-occlusive disease, infection or of idiopathic pulmonary hypertension. PHT may be an association with HLH and physicians treating HLH should be aware of this potential association. Pediatr Blood Cancer © 2012 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 11/2012; · 2.35 Impact Factor
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    ABSTRACT: While pre-emptive rituximab therapy for EBV has substantially reduced the incidence of post-transplant lymphoproliferative disorder, following allogeneic haematopoietic SCT (HSCT), cytomegalovirus (CMV) and adenovirus (ADV) still contribute to significant morbidity and mortality after HSCT. We therefore aimed to identify high-risk children who could benefit from recent advances in virus-specific immunotherapy, define the impact of viral reactivations on survival and estimate the economic burden of pre-emptive antiviral drug therapy. Between 2005 and 2010, prospective monitoring of 291 paediatric HSCT procedures revealed that reactivation of CMV (16%), ADV (15%) and EBV (11%) was frequent during period of CD4 T-cell lymphopenia (0.15 × 10(9) L(-1); P<0.05). We report significant risk factors for reactivation, most notably the use of serotherapy and development of GVHD (grade II) in the presence of pre-existing infection (ADV) or donor and/or recipient seropositivity (CMV, EBV). Most interestingly, CMV and ADV viraemia were the major independent predictors of mortality (P<0.05). CMV, ADV or EBV viral reactivation caused prolonged hospitalization (P<0.05), accounted for 15% of all mortality and substantially increased the cost of transplantation by ∼£22 500 ($34 000). This provides an economic rationale for targeting high-risk HSCT recipients with interventions such as virus-specific cell therapy.Bone Marrow Transplantation advance online publication, 26 November 2012; doi:10.1038/bmt.2012.221.
    Bone marrow transplantation 11/2012; · 3.00 Impact Factor
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    ABSTRACT: There is no literature regarding the outcomes of allogeneic hematopoietic cell transplantation (HCT) for patients with XIAP deficiency. In order to estimate the success of HCT, we conducted an international survey of transplant outcomes. Data was reported for 19 patients. Seven patients received busulfan-containing myeloablative conditioning (MAC) regimens. Eleven patients underwent reduced intensity conditioning (RIC) regimens predominantly consisting of alemtuzumab, fludarabine, and melphalan. One patient received an intermediate intensity regimen. Survival was poor in the MAC group, only 1 patient is surviving (14%). Most deaths were related to transplant related toxicities, including veno-occlusive disease and pulmonary hemorrhage. Of the 11 patients who received RIC, 6 patients are currently surviving at a median of 570 days following HCT (55%). Preparative regimen and HLH activity affected outcomes, and of RIC patients reported to be in remission from HLH, survival is 86% (p=0.03). We conclude that MAC regimens should not be used for patients with XIAP deficiency. It is possible that the loss of XIAP and its anti-apoptotic functions contributes to the high incidence of toxicities observed with MAC regimens. RIC regimens should be pursued with caution, and efforts should be made to ensure the remission of HLH prior to HCT if possible.
    Blood 11/2012; · 9.78 Impact Factor
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    ABSTRACT: Experience with allogeneic hematopoietic cell transplantation (HCT) of patients with XIAP deficiency is limited. We conducted an international survey to estimate outcomes. Nineteen patients underwent allogeneic HCT at a median age of 3 years (range 0.4-19). Twelve patients received reduced intensity conditioning (RIC) regimens and 7 received myeloablative conditioning (MAC) regimens. Patients received grafts from matched (n=11) or single allele mismatched (n=8) grafts. All but 2 grafts were from unrelated donors. Only 1 of the 7 patients who received MAC is surviving (14%), and 6 of the 12 patients who received RIC are surviving (50%), at a median of 414 days following HCT (range 139-1765). The most common causes of death included hepatic veno-occlusive disease, pneumonitis or ARDS, pulmonary hemorrhage, multi-organ failure, and sepsis. We conclude that the survival of patients with XIAP deficiency is poor compared to other forms of HLH and XLP. MAC regimens appear contraindicated.
    2012 Clinical Immunology Society Annual Meeting; 05/2012
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    ABSTRACT: A joint working group established by the Haemato-oncology subgroup of the British Committee for Standards in Haematology (BCSH) and the British Society for Bone Marrow Transplantation (BSBMT) has reviewed the available literature and made recommendations for the diagnosis and management of acute graft-versus-host disease. This guideline includes recommendations for the diagnosis and grading of acute graft-versus-host disease as well as primary treatment and options for patients with steroid-refractory disease. The goal of treatment should be effective control of graft-versus-host disease while minimizing risk of toxicity and relapse.
    British Journal of Haematology 04/2012; 158(1):30-45. · 4.94 Impact Factor
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    ABSTRACT: A joint working group established by the Haemato-oncology subgroup of the British Committee for Standards in Haematology (BCSH) and the British Society for Bone Marrow Transplantation (BSBMT) has reviewed the available literature and made recommendations for the diagnosis and management of chronic graft-versus-host disease (GvHD). This guideline includes recommendations for the diagnosis and staging of chronic GvHD as well as primary treatment and options for patients with steroid-refractory disease. The goal of treatment should be the effective control of GvHD while minimizing the risk of toxicity and relapse.
    British Journal of Haematology 04/2012; 158(1):46-61. · 4.94 Impact Factor
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    ABSTRACT: A joint working group established by the Haemato-oncology subgroup of the British Committee for Standards in Haematology and the British Society for Bone Marrow Transplantation has reviewed the available literature and made recommendations for the supportive care and management of organ-specific complications of chronic graft-versus-host disease (cGvHD). This guideline includes recommendations for the specific therapy of skin, oral, liver, gut, lung, ocular and genital manifestations of cGvHD and for the supportive care of these patients, including vaccinations and prophylaxis against infection. The goal of treatment should be effective control of GvHD while minimizing the risk of toxicity and relapse.
    British Journal of Haematology 04/2012; 158(1):62-78. · 4.94 Impact Factor

Publication Stats

2k Citations
490.90 Total Impact Points

Institutions

  • 2008–2014
    • University College London
      • • Institute of Child Health
      • • Department of Clinical, Educational and Health Psychology
      Londinium, England, United Kingdom
    • Columbia University
      • Department of Pediatrics
      New York City, NY, United States
    • Karolinska University Hospital
      Tukholma, Stockholm, Sweden
  • 2013
    • UK Department of Health
      Londinium, England, United Kingdom
  • 2000–2013
    • Great Ormond Street Hospital for Children NHS Foundation Trust
      • • Department of Bone Marrow Transplant
      • • Department of Immunology
      Londinium, England, United Kingdom
  • 2011–2012
    • The Newcastle upon Tyne Hospitals NHS Foundation Trust
      • Department of Paediatric and Adolescent Haematology and Oncology
      Newcastle-on-Tyne, England, United Kingdom
  • 2003
    • Imperial College London
      • Centre for Haematology
      London, ENG, United Kingdom