Full hematopoietic engraftment after allogeneic bone marrow transplantation without cytoreduction in a child with severe combined immunodeficiency

Abstract

IntroductionSevere combined immunodeficiency (SCID) involves a failure of T cells to proliferate to various stimuli and a failure of B cells to produce specific antibodies. 1,2 Adenosine deaminase (ADA) deficiency, an autosomal recessive genetic defect, produces a SCID phenotype. 3,4 The enzyme defect leads to an abnormality in purine nucleoside metabolism that interferes with lymphocyte viability and function. ADA-deficient SCID is characterized by growth delay, candidiasis, respiratory infections, opportunistic infections, and, without specific therapy, early death. 5 Low or absent ADA activity in erythrocytes or other cells is diagnostic.Bone marrow transplantation (BMT) is effective therapy for SCID. The profound T-cell dysfunction associated with ADAdeficient SCID prevents graft rejection and permits BMT without conditioning with an HLA-matched sibling donor. 1,2,6 Success rates are greater than 90%, with full recovery of T-cell and B-cell functions. 6 Complete T-cell engraftment is routinely demonstrated, and approximately 50% of patients demonstrate engraftment of donor B cells. 7 Without conditioning, host hematopoiesis persists with no evidence of myeloid or erythroid engraftment. 5,[7][8][9] Study design J.L., a 17-month-old girl, presented with fever, vomiting, cough, skin ulcers, a history of failure to thrive, recalcitrant thrush, chronic respiratory infections, and recurrent otitis media. Immunizations were current. Family history was negative for immunodeficiency. Physical examination revealed an ill-appearing white female with weight and height below the fifth percentile, a paucity of lymph nodes, and no hepatosplenomegaly.Laboratory evaluation revealed normal hemoglobin and platelet counts. The white blood cell count was 1600/cmm (normal, 6000-17 000/cmm) and consisted of 10% neutrophils, 20% lymphocytes, 65% monocytes, and 4% eosinophils. Liver function test results were normal. Titers were negative for human immunodeficiency virus, cytomegalovirus, hepatitis B virus, herpes simplex virus, Epstein-Barr virus, adenovirus, poliovirus, Toxoplasma, and Chlamydia trachomatis.ADA activity was deficient in erythrocytes and in peripheral blood mononuclear cells; purine nucleoside phosphorylase (PNP) activity was normal in both cell types (Table 1). Metabolic findings in erythrocytes were consistent with ADA deficiency, including elevated deoxyadenosine nucleotide (dAXP) of 0.491 mol/mL packed cells (normal, less than 0.002 M/mL), and reduced S-adenosylhomocysteine hydrolase activity of 0.42 nmol/h/mg protein (normal, 4.2 Ϯ 1.9). 3 A 3-year-old sister was HLA-identical (A2, A3, B35, B27, Cw2, Cw4, DRB1*01, and DRB1*04). Without myeloablative or immunosuppressive therapy, the patient was infused with 7.6 ϫ 10 8 unfractionated nucleated marrow cells per kilogram from her sister. After BMT, the patient engrafted rapidly, remained well, and required no blood products (Figure 1). Biopsy-proven grade I skin graft-versus-host disease (GVHD) developed at day 39 after BMT and resolved with topical corticosteroid...

Donor immune reconstitution after liver–small bowel transplantation for multiple intestinal atresia with immunodeficiency

“…16 Children with severe combined immunodeficiency who receive transplanted bone marrow from HLA-identical sibling donors without immunosuppression routinely demonstrate complete immune reconstitution. 17 In the present report, we show that an immunodeficient child undergoing LSBT from a 1-of-6 HLAmatched donor engrafted some donor hematopoietic and lymphoid progenitors but that after 2 years he has generated few donor CD3 ϩ CD4 ϩ and CD3 ϩ CD8 ϩ TCR ␣␤ T cells. Instead, most of the donor T cells are TCR ␥␦, have an IEL phenotype, and provide only partial immune correction.…”

Lymphodepleting effects and safety of pentostatin for nonmyeloablative allogeneic stem-cell transplantation1

“…Specimens were analyzed by polymerase chain reaction amplification for polymorphic markers (AmpFISTR Profiler PCR Amplification Kit; Perkin Elmer-Applied Biosystems, Foster City, CA) composed of short tandem repeats. Nine short tandem repeat markers were used, including D3S1358, vWA, FGA, TH01, TPOX, CSF1PO, D5S818, D13S317, D7S820, and the gender marker Amelogenin (10).…”

The hope and the reality of reduced intensity transplants in children with malignant diseases

“…2 Patients with severe combined immune deficiency routinely experience lymphoid engraftment in the absence of any form of pretransplant conditioning, 3 and full trilineage hematopoietic engraftment has been reported in such transplants. 4 The ability of the graft to eliminate residual malignant cells in the patient independent of the effects of pre-transplant conditioning has long been inferred from the increased leukemia-free survival rates in patients who received reduced graft-versus-host-disease prophylaxis after stemcell transplantation. More compelling evidence of the graftversus-leukemia effect was provided by the dramatic effect of donor lymphocyte infusions in patients with posttransplantation recurrences of chronic myelogenous leukemia (CML).…”