Biomedical subjects

Luigi Daniele Notarangelo

Publications and source records attributed to Luigi Daniele Notarangelo.

5 recordsLinked to original sources

PubMed2006

Combined decrease of defined B and T cell subsets in a group of common variable immunodeficiency patients.

Common variable immunodeficiency disease (CVID) is a primary immune disorder affecting B cells and characterized by hypogammaglobulinemia and recurrent infections. To elucidate the clinical and immunological heterogeneity of this condition, we have studied B and T cell subsets in 25 CVID patients. In eleven of them, we observed a remarkable relative expansion of a B cell subpopulation (CD19(hi)/CD21(lo) cells) characterized by the absence of CD23 and the reduced expression of the chemokine receptors CXCR5 and CCR7. Our analyses demonstrated in these patients that the expansion of CD19(hi)/CD21(lo) cells correlates with a selective decrease of circulating naïve and CD21(hi) memory B lymphocytes. The same group of patients displayed a simultaneous severe reduction of naïve CD4+ T cells associated with decreased levels of T cell receptor excision circles. These observations suggest that a combined defect in generation of B and T subpopulations may account for the abnormal immunophenotype characterizing this subgroup of CVID patients.

Adolescent↗

PubMed2005

Reduced thymic output, increased spontaneous apoptosis and oligoclonal B cells in polyethylene glycol-adenosine deaminase-treated patients.

Impairment of purine metabolism due to adenosine deaminase (ADA) deficiency is associated with a severe combined immunodeficiency (SCID). Polyethylene glycol-modified ADA (PEG-ADA) has provided noncurative, life-saving treatment for these patients, but full immune recovery is not achieved with this therapy. Since ADA-SCID is perhaps the most difficult form of SCID to handle clinically, understanding the benefits and limitations of PEG-ADA therapy may be relevant for treatment selection. To this purpose, we analyzed the rate of thymic output, T and B cell repertoires, number of T cell divisions, IFN-gamma and IL-4 production, and the extent of cell death in five ADA-SCID patients following a prolonged period of treatment with PEG-ADA. We found that thymic output was low in these patients. However, their T cell repertoire was heterogeneous, and their T lymphocytes produced cytokines upon activation and responded to mitogen stimulation, although with different kinetics. Furthermore, a high number of peripheral T lymphocytes were committed to apoptosis. Anomalies were also observed in the B cell compartment, with oligoclonal expansions of B cell clonotypes in two patients. Our data indicate that decreased thymic function, B cell oligoclonality, and increased spontaneous apoptosis may be the mechanisms by which the immunodeficiency of ADA-SCID patients persists in spite of treatment with PEG-ADA.

Adenosine Deaminase↗

PubMed2004

Mutations of the T-cell receptor constant region after in utero stem cell transplantation.

Like the immunoglobulin genes, the T-cell receptor genes are generated by rearrangements of non-contiguous genomic V, D and J regions, but unlike the immunoglobulin genes, somatic hypermutation is an infrequent event in T-cell receptor genes. Here, we describe the occurrence of spontaneous mutations in the constant regions of the T-cell receptor beta chains of T lymphocytes obtained from two babies who underwent in utero transplantation because of severe combined immunodeficiency. In view of the fact that in babies receiving transplants before birth, hematopoietic chimerism is consistently present, the lymphocytes are likely to be under chronic activation, which may represent a relevant biologic stimulus for generating the observed T-cell receptor hypermutation. This possibility is supported by the finding that the highest number of mutations was identified in clonally expanded T cells. These results provide further support indicating that hypermutation of the T-cell receptor genes may indeed occur, given the necessary conditions.

Adult↗

PubMed2004

Reconstitution of T-cell compartment after in utero stem cell transplantation: analysis of T-cell repertoire and thymic output.

BACKGROUND AND OBJECTIVES: In utero transplantation of hematopoietic stem cells allows immune reconstitution of fetuses with severe combined immunodeficiency. The objective of this work was to study the quality of T-cell reconstitution following this procedure. DESIGN AND METHODS: We evaluated the kinetics and extent of T-cell reconstitution in five infants with severe combined immune deficiency (SCID), three with a B+ and two with a B- phenotype, who received haploidentical stem cell transplantation before birth. To this end, we measured the frequency of T-cell receptor excision circles (TREC) and the diversity of the T-cell repertoire. RESULTS: In utero transplantation led to engraftment of donor-derived T lymphocytes which attained normal numbers in four infants, who are in good health. In the three patients with a B+ phenotype, generation of a heterogeneous T-cell repertoire was associated with development of TREC levels comparable to those of SCID patients treated by post-natal transplantation and of healthy babies. Of the two patients with a B- phenotype, one developed mixed T-cell chimerism and a substantial number of circulating T cells, associated with a variable heterogeneity of the T-cell repertoire; TREC levels were normal soon after birth, but declined thereafter. The remaining B- patient remained lymphopenic with a skewed T-cell repertoire and very low TREC levels. This patient eventually required transplantation from a matched unrelated donor at 5 years of age, but died of EBV-related lymphoproliferative disease. INTERPRETATION AND CONCLUSIONS: These data indicate that in utero transplantation of fetuses with B+ SCID allows generation of newly diversified T lymphocytes and ensures long-term reconstitution of cell-mediated immunity.

Adult↗

PubMed2003

Prospects for ultraviolet A1 phototherapy as a treatment for chronic cutaneous graft-versus-host disease.

BACKGROUND AND OBJECTIVES: Standard or investigative immunosuppressive therapies for cutaneous chronic graft-versus-host disease (GVHD) may prove not only ineffective but also cause serious adverse effects. Repeated exposure of the skin to ultraviolet radiation in the wavelength range 340-400 nm (so-called ultraviolet A1) was recently reported to have a strong local (intracutaneous) immunomodulatory activity. This study was undertaken to evaluate efficacy and safety of this phototherapy. DESIGN AND METHODS: Nine patients with cutaneous (4 lichenoid and 5 sclerodermoid) GVHD and mild or no other organ involvement were enrolled. All patients had developed serious drug toxicity and/or opportunistic infections. Phototherapy was administered three times a week. RESULTS: Complete remission was seen in 5 (2 lichenoid and 3 sclerodermoid) cases and a partial improvement in 4 (2 lichenoid and 2 sclerodermoid) after having received 15.8+/-3.8 (lichenoid GVHD) or 21.6+/-8.0 (sclerodermoid GVHD) sessions of phototherapy. Adverse effects were not registered. At follow-up (range: 6-25 months), two patients with sclerodermoid lesions relapsed after 5 months but responded to another treatment cycle. Patients with lichenoid GVHD showed relapses within one month and prolonged maintenance phototherapy was needed. Problems of drug toxicity and opportunistic infections improved as phototherapy allowed the reduction or interruption of systemic drug therapies. INTERPRETATION AND CONCLUSIONS: Ultraviolet A1 phototherapy may be considered as an appropriate therapeutic approach for sclerodermoid GVHD with no or mild involvement of internal organs. Patients with lichenoid GVHD should be treated only if they develop serious adverse effects to immunosuppressive therapies and opportunistic infections because of the carcinogenic hazard of high cumulative doses of ultraviolet A1 radiation.

Adult↗