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We report a 44-year-old patient with refractory acute myeloid leukemia who developed a rare form of disseminated cutaneous aspergillosis resulting from colonization in the deep reticular dermis of Aspergillus flavus. Diagnosis was based on cutaneous biopsy. Antifungal therapy was started with liposomal amphotericin B (L AmB). However, the lesions continued to spread and there was a marked decline in the patient's clinical condition. Consequently, L AmB was replaced with voriconazole. Response to voriconazole was excellent with regression of the skin lesions and a rapid improvement of the patient's general clinical condition.

Rationale: Phase I/II studies of autologous hematopoietic stem cell transplantation (HSCT) for multiple sclerosis ( MS) were initiated, based on results of experimental transplantation in animal models of multiple sclerosis and clinical observations in patients treated concomitantly for malignant disease., Patients: Eighty-five patients with progressive MS were treated with autologous HSCT in 20 centers and reported to the autoimmune disease working party of the European Group for Blood and Marrow Transplantation (EBMT). 52 (61 %) were female, median age was 39 [20-58] years. The median interval from diagnosis to transplant was 7 [1-26] years. Patients suffered from severe disease with a median EDSS score of 6.5 [4.5-8.5]. Active disease prior to transplant was documented in 79 of 82 evaluable cases., Results: The stem cell source was bone marrow in 6 and peripheral blood in 79, and stem cells were mobilized into peripheral blood using either cyclophosphamide combined with growth factors or growth factors alone. Three patients experienced transient neurological complications during the mobilization phase. The high dose regimen included combination chemotherapy, with or without anti-lymphocyte antibodies or, with or without, total body irradiation. The stem cell transplants were purged of lymphocytes in 52 patients. Median follow-up was 16 [3-59] months. There were 7 deaths, 5 due to toxicity and infectious complications, 2 with neurological deterioration. The risk of death of any cause at 3 years was 10 (+/-7)% (95 % confidence interval). Neurological deterioration during transplant was observed in 22 patients; this was transient in most but was associated with MS progression in 6 patients. Neurological improvement by > or = 1 point in the EDSS score was seen in 18 (21 %) patients. Confirmed progression-free survival was 74 (+/-12)% at 3 years being 66 (+/-23)% in patients with primary progressive MS but higher in patients with secondary progressive or relapsing-remitting MS, 78 (+/-13)%; p = 0.59. The probability of confirmed disease progression was 20 (+/-11)%. MRI data were available in 78 patients before transplant showing disease activity (gadolinium enhancing, new or enlarging lesions) in 33 %. Posttransplant MRI showed activity at any time in 5/61 (8 %) evaluable cases., Conclusion: Autologous HSCT suggest positive early results in the management of progressive MS and is feasible. These multicentre data suggest an association with significant mortality risks especially in some patient groups and are being utilised in the planning of future trials to reduce transplant related mortality.

Background and Objectives: Unrelated donor bone marrow transplant (UD-BMT) has become an attractive, alternative source of hematopoietic cells for patients lacking a matched sibling. The aim of this paper is to report on 520 patients below 19 years of age undergoing UD BMT in 31 Italian centers between September 1989 and December 2001, and to focus on the results achieved in the 423 patients grafted before December 2000., Designs and Methods: In 1989 the Italian Bone Marrow Transplant Group (GITMO) and the Italian Association for Pediatric Hematology and Oncology (AIEOP) established the Italian Bone Marrow Donor Registry (IBMDR) to facilitate donor search and marrow procurement for patients lacking an HLA identical sibling. By the end of December 2001, 296,720 HLA-A, B typed volunteer donors had been cumulatively registered and 3,411 searches had been activated for Italian patients. At least one HLA-A, B, DRB1 matched donor was found for 54% of the patients and 520 UD BMTs were performed in patients below 19 years of age before December 2001. Since 1999 more than 90% of the patients < or = 14 years old, and more than 50% of the patients 15-18 years old undergoing UD BMT have been treated in AIEOP institutions. In 50% of the cases donors were found in the IBMDR, and in 50% they were found in 14 other Registries. The average time from search activation to transplant was 6 months for diseases other than chronic myeloid leukemia (CML), while for CML it was 8.7 months., Results: Actuarial 100-day transplant-related mortality (TRM) was 32% in patients grafted between 1989 and 1997, and 21% for patients grafted after 1998 (p = 0.003). Twenty-eight per cent of the patients developed grade III or IV acute graft-versus-host disease (GvHD), and 20% developed extensive chronic GvHD. The rate of disease-free survival at three years was 37% for patients with acute lymphoblastic leukemia, 38% for acute myeloid leukemia or myelodysplastic syndrome patients, 59% for patients with inborn errors, and 51% for patients with CML., Interpretation and Conclusions: We conclude that the IBMDR has benefited a substantial number of patients lacking a matched sibling and has facilitated the recruitment of UDs into the international donor pool. Results show a positive trend after 1998, mainly due to a decrease in transplant-related-mortality.

Background and Objectives: Allogeneic bone marrow transplantation (BMT) is a widely accepted therapeutic approach in homozygous beta-thalassemia. However, the majority of patients do not have a genotypically identical donor within the family. This prompted us to conduct a pilot study to investigate the feasibility of matched unrelated bone marrow transplantation in thalassemia. The major drawback was the high risk of immunologic and transplant-related complications, mainly graft-versus-host disease (GvHD) and graft failure., Design and Methods: Our aim was to reduce this risk through careful selection of donor/recipient pairs. HLA haplotypes that show a high linkage disequilibrium among their class I, class II and class III alleles are considered extended or ancestral haplotypes., Results: These haplotypes are conserved and can be shared by apparently unrelated individuals. Our study shows that matching for these haplotypes significantly improves the outcome of unrelated bone marrow transplantation in thalassemia. In fact, results were comparable to those obtained in transplants using HLA-identifical family donors., Interpretation and Conclusions: Better results were obtained in patients with lesser iron overload and when the donor shared an identity for the DPB1 alleles.

Allogeneic bone marrow transplantation (BMT) from a genotypically identical family donor is an accepted therapeutic option for homozygous beta-thalassemia. However, only a minority of patients have access to this curative procedure. The aim of this study is to explore the feasibility of matched unrelated transplants in thalassemia and the possibility of reducing the risk of immunologic complications through careful selection of donor/recipient pairs. Since November 1992, 32 patients (age range, 2-28 years) have been enrolled. There were 4 patients assigned to risk-class I, 11 to risk-class II, and 17 to risk-class III of the Pesaro classification. Extended haplotype analysis and family segregation studies were employed for identification of suitable donors. Of the 32 donor/recipient pairs, 24 were identical for HLA-A, B, C, DRB1, DRB3, DRB4, DRB5, DQA1, and DQB1 loci; 7 pairs were identical for 2 extended haplotypes, and 15 pairs shared one extended haplotype. Grade II-IV acute graft-versus-host disease (GVHD) developed in 11 cases (41%) and chronic GVHD in 6 (25%) out of 24 patients at risk. There are 22 patients (69%) who are alive and transfusion-independent after a median follow-up of 30 months (range, 7-109 months). There were 6 patients (19%) who engrafted and subsequently died from transplant-related complications. In 4 cases (12.5%) graft rejection was observed within 30 days and it was followed by autologous reconstitution. Out of 22 patients with a donor identical for at least one extended haplotype, there are 19 who survived, 17 of them being transfusion-independent. Among the 10 recipients who did not share any extended haplotype with the donor, only 5 are alive without thalassemia and 3 patients died. Of the 6 patients who died, 5 belonged to risk-class III and only 1 to risk-class II. BMT from well-selected unrelated donors may offer results comparable to those obtained in transplantations using HLA-identical family donors, especially for patients with lesser iron overload.

Background and Objectives: Unrelated donor bone marrow transplant (UD-BMT) has become an attractive alternative source of hematopoietic cells for patients lacking a matched sibling. The aim of this paper was to report on results of the 696 UD BMTs performed in 31 Italian institutions during the first 10 years of activity of the Italian Bone Marrow Donor Registry (IBMDR)., Evidence and Information Sources: In 1989 the Italian Bone Marrow Transplant Group (GITMO) established the IBMDR to facilitate donor search and marrow procurement for patients lacking an HLA identical sibling. By end of December 1999, 260,000 HLA-A, B typed volunteer donors had been cumulatively registered and 2,620 searches had been activated for Italian patients. At least one HLA-A, B, DRB1 matched donor was found for 54% of the patients and 696 UD BMTs were performed. In 50% of cases the donor was found in the IBMDR and in 50% in 15 other Registries. The average time from search activation to transplant was 6 months for disease other than CML. For CML it was 14 months. Actuarial 12-month transplant-related mortality (TRM) was 68% in patients grafted between 1979 and 1992 and 44% for patients grafted after 1993. Twenty-eight per cent of patients developed grade III or IV acute GvHD and 24% developed extensive chronic GvHD. The rate of disease free survival at three years was 57% for patients with 1st chronic phase CML, 37% for patients with 1st or 2nd CR ALL, 31% for AML or MDS patients 18 years of age and 54% for patients with inborn errors., Perspectives: We conclude that the IBMDR has benefited a substantial number of patients lacking a matched sibling and has facilitated the recruitment of UDs into the international donor pool. The long time required for the search is the major obstacle to the success of this programme. This suggests that early transplant and a decrease in TRM could further improve these encouraging results.

Unrelated donor bone marrow transplant (UD-BMT) has become an attractive alternative source of hematopoietic cells for patients lacking a matched sibling. The aim of this paper was to report on results of the 696 UD BMTs performed in 31 Italian institutions during the first 10 years of activity of the Italian Bone Marrow Donor Registry (IBMDR). In 1989 the Italian Bone Marrow Transplant Group (GITMO) established the IBMDR to facilitate donor search and marrow procurement for patients lacking an HLA identical sibling. By end of December 1999, 260,000 HLA-A, B typed volunteer donors had been cumulatively registered and 2,620 searches had been activated for Italian patients. At least one HLA-A, B, DRB1 matched donor was found for 54% of the patients and 696 UD BMTs were performed. In 50% of cases the donor was found in the IBMDR and in 50% in 15 other Registries. The average time from search activation to transplant was 6 months for disease other than CML. For CML it was 14 months. Actuarial 12-month transplant-related mortality (TRM) was 68% in patients grafted between 1979 and 1992 and 44% for patients grafted after 1993. Twenty-eight per cent of patients developed grade III or IV acute GvHD and 24% developed extensive chronic GvHD. The rate of disease free survival at three years was 57% for patients with 1st chronic phase CML, 37% for patients with 1st or 2nd CR ALL, 31% for AML or MDS patients < or = 18 years of age and 54% for patients with inborn errors. We conclude that the IBMDR has benefited a substantial number of patients lacking a matched sibling and has facilitated the recruitment of UDs into the international donor pool. The long time required for the search is the major obstacle to the success of this programme. This suggests that early transplant and a decrease in TRM could further improve these encouraging results.

Background and Objective: Transplantation of hematopoietic stem cells from different sources is being increasingly used to treat a variety of diseases in children. Transplant procedures and indications have changed considerably during recent years. Monitoring of information about these changes is useful for interpretation of nationwide collected data., Design and Methods: Since 1985, Centers belonging to the AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica), performing hematopoietic stem cell transplants (HSCT) in children, and members of the AIEOP-Bone Marrow Transplant (BMT) Group annually report data on their transplant activity to the AIEOP-BMT Registry employing specially prepared patient-oriented forms., Results: From January 1985 to December 1998, a total of 2,474 bone marrow (BM), peripheral blood (PB) or umbilical cord blood (CB) transplants were reported: 1,296 (52%) were allogeneic (Allo) and 1,178 (48%) autologous (Auto) transplants. These transplants were performed in 19 Italian Centers on 2,249 patients aged less than 17 years. Among Allo-transplants, 1,198 (92%) were performed using BM progenitor cells, whereas 49 (4%) CB, 42 (3%) were PB, 4 BM plus PB, and 3 BM plus CB allografts; they were performed using HLA-identical sibling donors in 867 cases (67%) and alternative donors (i.e. partially-matched relatives or unrelated donors) in the remaining 429 (33%) cases. Allogeneic transplants were performed on 786 (67%) patients with malignancy and on 395 (33%) patients with non-malignant disorders. In the last 6 years, the number of Allo-transplants per year exceeded that of Auto-transplants. Of the Auto-transplants, 775 (66%) were performed using BM, and 403 (34%) using PB alone or combined with BM hematopoietic stem cells. Indications for Auto-BMT were myelo-lymphoproliferative disorders in 524 (49%) cases, solid tumor in 533 (50%) cases and non-malignant disease in 11 (1%) cases. In the last 5 years, the use of PB for autografts has increased from 7% to 70%., Interpretation and Conclusions: These data reflect the development and present status of HSCT in Italy and provide a basis for patient counseling and health care planning.

Between January 1989 and July 1995 the search for an unrelated donor (UD) was started for 379 consecutive Italian patients with Philadelphia positive (Ph+) chronic myelogenous leukaemia (CML). 89 (23%) were transplanted. The overall probability of transplant before and after December 1991 was 16% and 49%, respectively (P=0.0001), and average interval between search activation and graft was 23 months and 13 months, respectively (P=0.0001). Disease-free survival (DFS) following 60 consecutive transplants performed before February 1996 was 41.5% at 48 months and was 64% for patients grafted after January 1993. In univariate analysis, five variables had a favourable effect on DFS: year of bone marrow transplantation (BMT) after 1993 (P=0.0002), HLA-DRB1 donor/recipient (D/R) match (P=0.0006), total body irradiation (TBI) containing regimen (P=0.0006), graft-versus-host disease (GvHD) prophylaxis including 'early' cyclosporin before the transplant, and a marrow cell dose > 3 x 10(8)/kg of recipient body weight (P=0.04). Multivariate analysis confirmed that HLA identity (P=0.006), TBI-containing regimen (P=0.0001) and 'early cyclosporin' (P=0.04) were associated with higher DFS. Transplant-related mortality (TRM) was 67% in patients grafted before January 1993 and 30% in patients grafted subsequently (P=0.002). Multivariate analysis confirmed DRB1 identity (P=0.03) and TBI-containing regimen (P=0.0005) to be independent factors predictive of low TRM. This suggests that the outcome of patients transplanted from an HLA DRB1 matched donor, after a TBI-containing preparative regimen, is similar to results recently reported in patients transplanted from geno-identical siblings. These results indicate that the search should be initiated at diagnosis for patients < 45 years of age and UD BMT should be considered early in the disease course for those with an available DRB1-matched unrelated donor.

From December 1989 to December 1997 40 children aged 1 year to 19 years with inborn errors other than severe combined immunodeficiencies underwent unrelated donor (UD) bone marrow transplantation (BMT) in one of 10 institutions of the Italian Bone Marrow Transplant Group participating in this program. The diseases leading to BMT included Fanconi Anemia (10), Thalassemia (8), Wiskott Aldrich syndrome (5), haemophagocytic lymphohystiocytosis (6), osteopetrosis (3), storage diseases (6), Chediak Higashi syndrome (1), Schwachman syndrome (1). Thirty-three pairs were A, B, DRB1 matched. Three pairs were one antigen mismatched and one pair was two antigens mismatched. The remaining three pairs lacked information on molecular biology. Twelve children underwent a preparative regimen including radiotherapy. The remaining 28 children were conditioned with a chemotherapy regimen which included Busulfan. GvHD disease prophylaxis included CSA and MTX alone (9) or associated with ALG (17) or in vivo Campath 1G (12). The remaining two children received CSA alone. Thirty-five children showed donor engraftment; three children with thalassemia and one with osteopetrosis failed to engraft. Five children developed secondary graft failure. Actuarial 5 year disease-free survival was 62%; grade III-IV acute GvHD developed in seven of 38 evaluable children (18%); chronic GvHD developed in seven of 27 evaluable children (26%). We confirm that Wiskott Aldrich syndrome, HLH, and osteopetrosis represent an absolute indication for UD-BMT. Prognosis of UD-BMT for FA could improve in children grafted in an early phase, but a better preparative regimen has to be identified. UD-BMT in thalassemia is acceptable only in a restricted subset of patients selected for poor compliance to therapy.

HLA class II antigens and DRB1, DQA1, DQB1 alleles were studied in 16 Italian and in 16 Sardinian patients with pemphigus vulgaris (PV). In the last group the complete HLA A-DQ haplotypes, including the complotypes, were defined by family studies. As in other populations, two PV susceptibility haplotypes were found: HLA-DRB1*0402, DQA1*0301, DQB1*0302 and HLA-DRB1*1401, DQA1*0104, DQB1*0503. The first haplotype was largely prevalent in the Sardinian patients and was a part of the extended haplotype HLA-A2, Cw4, B35, S31, DR4, DQ8. The strength of the allele associations to PV is in agreement with the view that the main PV susceptibility genes are the DRB1*0402 and DQB1*0503 alleles. A genetic resistance to PV seems to be conferred by the HLA-DR3, DQ2 haplotype in the Sardinian population.

We report a case of BMT from an unrelated donor (MUD) in a patient affected by Wiskott- Aldrich syndrome (WAS). The donor-recipient pair was completely identical for two HLA-extended haplotypes. The conditioning regimen consisted of Bu 14 mg/kg followed by CY 200 mg/kg. GVHD prophylaxis was carried out with CsA plus short-term MTX. Allogeneic engraftment was obtained without any signs of acute or chronic GVHD. At fifteen months from the transplant the patient was in an excellent clinical condition. This case confirms the role of BMT from MUD in WAS, and suggests that complete donor-recipient identity for two entire HLA-extended haplotypes is a particularly favorable immunogenetical condition in this type of transplant.

From 1 September 1988 to 30 September 1993, a search for an unrelated donor (URD) was started for 633 Italian patients. Eighty-five of them (13%) were transplanted. Despite the introduction of more strict criteria for the selection of compatible donors, the percentage of patients who reached transplant increased significantly after December 1992. For patients who started a search before and after January 1993, respectively the probability of transplant by 8 and 16 months from search activation was 4 and 10%, compared to 22 and 37% (P = 0.0001). The average intervals between search activation and graft were 15 and 8 months respectively, for the first and second group (P = 0.0001). Data of 75 consecutive transplants performed up to March 1994 were analyzed. Actuarial 2-year survival was 15% for patients grafted before 1992 and 40% for those grafted after January 1992. In this latter period, survival of patients with malignant and non-malignant disorders was 32 and 67%, respectively. In univariate analysis, patients younger than 16 years (P = 0.01), patients grafted after 1992 (P = 0.01) and patients receiving the marrow from a 6-antigen matched donor (P = 0.01) showed a higher survival probability. Multivariate analysis did not show any difference, probably due to the low number of patients and to short follow-up. The adoption of stricter and more accurate HLA-matching criteria and the consequent reduction of deaths related to acute GVHD were the main reasons for the improvement of survival observed in patients grafted after 1992.

No data are available on the presence and frequency of peripheral or central joint disease, routinely determined by bone scintigraphy with 740 MBq of [99mTc]MDP, in adult celiac disease. Bone scintigraphy was carried out to detect early acute inflammatory lesions in 22 adult celiac patients (15 females and seven males; mean age 36.72 years, range 17-63). Bone scintigraphy was positive for sacroiliitis in 14 cases (63.6%). Except in the case of one patient suffering from rheumatoid arthritis, laboratory data were normal. Our data suggest that as in other chronic intestinal diseases, celiac disease in adults, is frequently associated with central joint disease. This high incidence of sacroiliitis, the joint disease most frequently found in our patients, has not been previously reported in other series. We believe, therefore, this difference could be explained by the different methodology used for the screening of joint disease.

The Sardinian population in many aspects differs from other Caucasoid populations, particularly for its degree of homogeneity. For this reason we have studied 50 adult Sardinian patients with celiac disease (CD) and 50 control healthy Sardinian individuals by RFLP analysis and by extensive oligotyping for 17 HLA-DPB1, 8-DQB1 and 9-DQA1 alleles, and established their -DPB1 alleles and -DQB1 -DQA1 genotypes. The heterodimer HLA-DQB1*0201/-DQA1*0501, present in 96% of our patients, is strongly associated with CD susceptibility, confirming published reports. On the other hand we found in 11 of 50 probands (22%) the presence of the allele -DQB1*0502/DQA1*0102. This genotype is extremely rare in other Caucasian populations and appears to confer limited protection in CD Sardinian patients.

HLA-A, B, Cw, DR and DQ antigens were serologically determined in 105 patients suffering from lichen planus (LP). Of these patients, 87 had idiopathic LP and 18 had secondary LP. In the first group, 43 had cutaneous LP without mucosal lesions, 17 had cutaneous LP with mucosal lesions and 27 had purely mucosal LP. No HLA antigen was found to be significantly associated with secondary LP or with mucosal idiopathic LP. In cutaneous idiopathic LP with or without mucosal lesions, the HLA-DR1 and DQ1 antigen frequency was significantly increased, and that of HLA-DQ3 significantly decreased. Among the HLA-DR1 cutaneous idiopathic LP patients, 78.5% carried the DRB1*0101 allele, and 21.4% the DRB1*0102 allele, compared with 35.7 and 67.8%, respectively, of the HLA-DR1 controls. Our data demonstrate that idiopathic LP is influenced by HLA-associated genetic susceptibility and resistance factors not involved in secondary LP, and that cutaneous idiopathic LP is a genetically and therefore pathogenetically different condition from purely mucosal idiopathic LP.

We treated 18 heavily iron-loaded patients who had become ex-thalassaemics after bone marrow transplantation with subcutaneous desferrioxamine therapy for 5-20 months. As determined using serum ferritin concentration, transferrin saturation and stainable liver iron obtained in follow-up biopsies, marked decreases in body iron stores were observed with this regimen. Moreover, the liver function tests demonstrate a trend to normalization in all cases. Local skin reactions to desferrioxamine were the only toxicities observed. We conclude that pharmacological iron chelation is a safe and effective therapy in the reduction of iron deposits in this clinical situation; it therefore represents a valid alternative to phlebotomy in selected patients.

Serological studies have demonstrated that lichen ruber planus is associated with the HLA-DR1 antigen. This association was also confirmed by us in the Sardinian population. To establish which DRB1 molecular alleles are involved, we studied a selected group of 14 DR1 positive patients affected by cutaneous idiopathic lichen planus and a group of DR1 positive healthy controls using PCR with sequence-specific primers (PCR-SSP). Comparisons between the allele frequencies in patients and controls showed a positive association with cutaneous idiopathic lichen planus for the DRB1*0101 allele (RR = 5.8, P = 0.0097), DRB1*0101 and DRB1*0102 are associated with the same DQA1 and DQB1 alleles and are different only for two amino acids in positions 85 and 86 of the DRB1 gene. In our case report predisposition to cutaneous idiopathic lichen planus is correlated with a valine in position 85 and a glycine in position 86 at the second exon of the DRB1 gene.

A 16-year-old Sardinian girl affected by homozygous beta-thalassaemia was submitted to allogeneic BMT using an HLA-identical, MLC-negative, unrelated donor. The donor and the patient were homozygous for the entire extended haplotype A30, Cw5, B18, F130, DRB1*0301, DRB3*0202, DQA1*0501, DQB1*0201 and heterozygous for DPB1*0301/DPB1*0202. The conditioning regimen consisted of 14 mg/kg busulphan and 160 mg/kg cyclophosphamide. Engraftment was achieved 14 days from BMT and the haematological reconstitution was complete without any signs of acute or chronic GVHD. Seven months after the transplant the patient was in excellent general condition. The hypothesis is advanced that when two HLA extended haplotypes are shared by donors and recipients, particularly in homozygosity, this is a very favourable immunogenetic condition in unrelated BMT.

The HLA-B49 DR4 haplotype, which is rare in Caucasoid populations, has a frequency in Sardinia of approximately 6% and a very strong linkage disequilibrium (LD). To better understand its genetic structure, the Bf, C4A and C4B Class III alleles were studied in 56 healthy unrelated Sardinian subjects of B49 DR4 phenotype and in 24 of their families. Moreover, 14 sick subjects with the same phenotype were examined together with five of their families. A group of 285 haplotypes belonging to randomly selected individuals was used as a control population sampling. The distribution of the Bf, C4A and C4B alleles among the healthy probands revealed two main groups of association: one major group of 36 subjects (64.3%) with the BfF, C4A3 and C4B4 alleles and one minor group of 14 subjects (25%) with BfS, C4AQ0 and C4B1. A similar subdivision was also observed in the small group of patients. The family analysis confirmed these results and showed two different B49 DR4 extended haplotypes: one with the F34 complotype in 79.1% of the probands (delta x 1000 = 49.0) and the other with the S01 complotype in 20.8% of the probands (delta x 1000 = 17.3). The first one, in LD with the A1 and Cw7 alleles, has not yet been reported in other populations. The second one seems to be identical to a haplotype already reported in the Spanish population. The molecular analysis of the DRB1 locus carried out in 20 of the 70 probands demonstrated that, in both haplotypes, DR4 was represented by the DRB1*0405 allele.(ABSTRACT TRUNCATED AT 250 WORDS)

A 25-year-old woman with AIDS was submitted to HLA-identical allogeneic BMT after cytoablation with busulphan and cyclophosphamide and combined anti-HIV-1 therapy with zidovudine, IFN-alpha 2 and anti-HIV-1-specific T cell clones. Marrow engraftment occurred after 18 days and tests for HIV-1 were negative after 30 days but the hematologic reconstitution of the patient was poor. A second BM infusion from the same donor was ineffective and treatment with GM-CSF only induced a transient increase of the blood cell count, suggesting iatrogenic damage to the BM microenvironment. The development of ARDS led to the death of the patient 10 months after transplantation. Post-mortem investigation did not reveal any active infections and PCR on autopsy tissues was negative for HIV-1.

With the aim of searching for HLA haplotypes and non-B27 allele frequency variations in Sardinian AS patients, HLA-A, B, Cw, DR, DQ and Bf, C4A and C4B typing and haplotype assignment was carried out in the families of 25 AS patients and in 44 healthy individuals, all B27 heterozygotes. In the AS patients a significant increase of the A2, Cw2, B27, DR2, DQ1 haplotype was found. This depends only partially on the linkage disequilibrium existing in the Sardinian population between B27 and the other alleles of this haplotype, and rather seems to be due to a primary association of Cw2 and DR2 alleles with AS. Preliminary data seem to show that this haplotype bears the S31 complotype and the DRB1*1601 allele both in the AS patients and in the healthy controls. The pathogenetic implications of these findings are discussed.

A study on the HLA structure of the Sardinian population was carried out on 551 healthy unrelated families representing all of the island districts. Altogether 2202 HLA-A, B, Cw, DR individual haplotypes and 853 different haplotypes were determined. Cavalli-Sforza and Edwards' genetic distance index for the total of 62 tested alleles showed a modest heterogeneity between one district and another (0.09-0.16). The genetic distance between Sardinians and the rest of the Italian population was 0.23 (0.22-0.26) and progressively increased in comparisons with caucasoids (0.26), negroids (0.34) and mongoloids (0.41). Sixty-three two-locus haplotypes with a high positive linkage disequilibrium were observed in our family sample. The percentages of two-locus haplotypes in LD shared with other populations turned out to be 45% with caucasoids, 20% with negroids and 10% with mongoloids. The distribution of the A, B, Cw, DR haplotypes is shown with 673 of them represented only once or twice, and 10 (1.2%) 14-322 times each. Of the latter, 8 are extended haplotypes, 6 of which characterize the Sardinian population. The analysis of our data suggests that the present-day Sardinian population is the result of a superposition of different populations, mainly consisting of caucasoids on a pre-caucasoid paleo-Mediterranean substratum.

479 families, each with a proband affected by homozygous beta-thalassemia, were typed for HLA. 224 families with a total of 1020 members were typed for the HLA-A, B, C, DR and DQ loci and 255 families with 1046 family members, were typed for the HLA-A, B, and C loci. Altogether, 896 A, B, C, DR and DQ haplotypes and 1020 A, B and C haplotypes were defined. At the same time, 120 healthy unrelated individuals from the same population were typed and used as controls. The analysis of the results was carried out at antigen, allele, haplotype, genotype and sex ratio level with the aim of looking on the one hand, for the existence of heterogeneity between the probands, the unrelated individuals and the healthy siblings and, on the other, for the existence of any distortion whatsoever of the HLA segregation in either the probands or in the healthy siblings in respect of the expected values according to the Mendelian equilibrium. No significant differences were evident between the probands and the controls by the tests carried out at different levels of the HLA system. This leads us to exclude the existence of an association between beta-thalassemia and HLA in the population studied. Moreover, the analysis of the transmission of the alleles, the haplotypes, the genotypes and the sex-ratio by parents to both affected and to healthy children did not show any clear evidence of segregation distortion in respect of the theoretical values.

HLA Class I and Class II antigens were studied in 103 unrelated Sardinian patients with Graves' disease (GD), 71 of whom had ophthalmopathy, and in 220 healthy controls. Molecular typing of the DQB1 allelic variants was carried out on 34 GD patients and 35 healthy controls, selected for the HLA-DR2-DQw1 phenotype. The results of the serological typing showed a positive association with the DR2 and the DQw1 antigens and a negative association with DR3 and DQw2 antigens. These associations were stronger in the GD patients with ophthalmopathy. The DQB1 molecular analysis in patients with the HLA-DR2-DQw1 phenotype revealed the presence of the DQB1*0502 allele in 91.1 per cent of the patients and in 82.2 per cent of the controls. In the Sardinian population GD seems to present a different HLA association than that observed in other Caucasian populations (DR3-Dw24). The DR2 and DQw1 positive associations may be explained by the high frequency of the DQB1*0502 allelic variant (37.7 per cent) which is rare in the other Caucasian populations. The absence of an association between DR3 and GD in Sardinia can be attributed to the very low frequency of the HLA-B8-DR3 (Dw24) haplotype. In fact, in the Sardinian population, DR3 is associated with the allelic variant Dw25 carried by the HLA-B18-DR3 haplotype.

Background: In this work we investigated whether serologically HLA class II compatible donor-recipient pairs showed differences in restriction fragment length patterns, and whether there is a correlation between the genomic differences observed and the incidence of rejection and acute graft versus host disease (GVHD)., Methods: High molecular weight DNA was extracted from thirty-three transplanted thalassemic patients and from their genotypically HLA identical donors. The DNA was digested with TaqI and PstI restriction enzymes, separated by horizontal electrophoresis and transferred onto nylon filters., Results: Differences at the molecular level were observed in only one patient, who rejected the transplant respect to his donor when DNA was digested with the TaqI restriction enzyme and hybridized with DPB cDNA probe., Conclusions: Although the molecular analysis revealed a difference between a patient who rejected the transplant and his donor, the RFLP typing confirmed the serological identity of the HLA class II antigens in all the other donor-recipient pairs studied.

This study was carried out in Sardinia, an Italian region with a very high IDDM incidence. HLA class I and class II antigens were studied in 97 unrelated IDDM patients, 33 complete families with at least one affected member each, and 559 healthy controls. Molecular typing of the DQB1 alleles was carried out in 31 patients and 61 controls. The haplotypes were determined by family studies. The HLA-DR3, DQw2, and DR4 antigens were positively associated with IDDM. The DR3 antigen was nearly always associated to B18 and frequently carried by the extended haplotype A30 Cw5 B18 3F130 DR3 DQw2. The genotype analysis of the patients showed a strong increase of the DR3/DR4 heterozygotes with a relative risk higher than that of the DR3 and DR4 homozygotes. The DR2 antigen was negatively associated with IDDM in the central island districts but not in the southern districts. The DQB1 molecular analysis showed only three alleles in the patients: DQB1*0201 (75.8 per cent), DQB1*0302 (16.1 per cent), and DQB1*0502 (8.1 per cent). These alleles are non Asp 57, so it would seem that nearly if not all Sardinian IDDM patients are NA/NA homozygotes. The DQB1*0502 allele, extremely rare in other Caucasian populations, represents in Sardinia about 70 per cent of the HLA-DR2 haplotypes, contributing to the increase of the pool of IDDM susceptible genes. Moreover it is carried in 27 per cent of the DR2 positive individuals with the extended haplotype A2 Cw7 Bw58 3F31 DR2 DQw1.AZH.

A 12-week trial was carried out to compare the efficacy of pirazolac (300-600 mg b.i.d.) with that of indomethacin (25-50 mg t.i.d.) in patients with ankylosing spondylitis. A total of 119 patients completed the treatment period, with 32 drop-outs. Both therapies showed significant improvements in clinical symptoms.

We report a case of classical Kaposi's sarcoma (KS) in a patient affected by B-cell chronic lymphocytic leukemia for 2 years and who had not received any antiblastic treatment. At the ultrastructural analysis the leukemic cell showed rather immature features, and the immunologic phenotype (absence of detectable cytoplasmic Ig, and expression only of the DR, B2 and IgD lambda molecules on the surface membrane) proved its intermediate level of maturity, its monoclonality and relative rarity. The patient presented a complex immunologic deficiency, revealed not only by the monoclonality of the B lymphocytes and their low degree of maturity, but also by the almost total absence of T helper lymphocytes, by the high reduction in NK activity, by the very scarce proliferative response to the polyclonal mitogens PHA, ConA and PWM, and by a complete anergy to the skin test of delayed reactivity. The search for antibodies against the viruses EBV, CMV, HTLV-I and HTLV-III in the serum was negative. At the HLA typing, the patient was DR5, as are most classical KS and/or B-CLL patients. The data are discussed in relation to documented non-casual association between B-CLL and KS. We stress that immunosuppression may play an important role in the pathogenesis of both diseases and the possibility of their being conditioned by common genetic HLA-associated factors of predisposition.

The presence of HLA-associated genetic factors in patients with multiple skin carcinomas was investigated. 43 patients affected by multiple basal and squamous cell carcinomas and 220 healthy age-matched controls were typed for 72 HLA-A, B, C, DR antigens. A negative association of B-17 (mostly B-58) and a positive association of Cw-3 and DR-1 was observed in patients with multiple basal cell carcinomas; a similar negative association with B-58 and positive association with DR-1 was seen in patients with squamous cell carcinomas. The results of this study suggest the presence of resistance factors to the development of skin cancers associated with B-17 (B-58) antigen.

Familial mediterranean fever (FMF) is an hereditary disorder characterized by attacks of febrile serosal inflammation involving pleura or peritoneum and synovium, followed usually by insidious onset of amyloidosis. In other patients amyloidosis of AA-type is the only finding of the disease. This disorder is common in Jews of Sephardi and Ashkenazi ancestry, Arabs, Armenians and Turks. In this work the clinico-biological features and the therapeutical aspects of a patient, suffering from FMF, of Italian ancestry are presented.

T lymphocyte subsets, mitogenic response, and immunoglobulin levels were studied in peripheral blood from 95 thalassemic patients before and at different times after bone marrow transplantation. With the exception of patients receiving more than 100 transfusion units before transplant, who showed an increased percentage of CD8-positive cells, thalassemic patients were essentially immunologically normal. Depressed lymphocyte proliferative response to phytohemagglutinin, concanavalin-A, and pokeweed mitogen; decreased IgG, IgM and IgA levels; and abnormal T subpopulation distribution were observed early after transplant. Long-term transplanted patients showed complete recovery of the immunological profile with the exception of the IgA levels, which were significantly decreased up to 2 years after transplant.

Twelve Sardinian patients affected by histologically defined classic Kaposi's sarcoma (KS) were HLA-A, B, C and DR typed. Compared to 220 age and ethnically matched healthy controls, KS patients showed a significant increase in HLA-DR5 (66.6 vs 23.1%, P less than 0.001) and a considerable decrease in HLA-DR3 (8.3 vs 53.6%, P = 0.0055). No definite association was observed for other HLA antigens. These results confirm the existence of an HLA associated genetic control of KS susceptibility and support the hypothesis that HLA-DR5 plays the role of a predisposition marker while HLA-DR3 bears a genetic resistance to the disease.

Increased iron storage represents a characteristic condition in patients with beta zero-thalassaemia intermedia. Iron overload is an important factor in cellular damage. Recent studies have shown an enhanced lysosomal fragility due to increased iron storage. 13 patients with beta-thalassaemia intermedia, aged 17-44 years, were studied. Both serum ferritin and serum N-acetyl-beta-D-glucosaminidase levels were evaluated in all subjects studied. A significant linear correlation (P less than 0.05) between serum ferritin and serum N-acetyl-beta-D-glucosaminidase levels were found.

The genomic DNA of 25 unrelated individuals with HLA haplotype A30 Cw5 B18 BfF1 DR3 D w52 DQw2 was digested with the restriction enzyme Taq I and hybridized with cDNA probes for C4 and 21-OH genes. Eighteen individuals and a non-Sardinian reference cell (DUCAF) were homozygous for the entire extended haplotype, six individuals were heterozygous for the HLA-A locus and homozygous for the rest of the same haplotype. All of the 18 homozygous individuals, four of the six heterozygous subjects and the DUCAF cell revealed the absence of two fragments at 3.2 and 2.4 kb corresponding to the 21-OH A gene, and the absence of fragments corresponding to the C4 B "long" or "short" gene. The contemporary absence of the 21-OH A and C4 B genes seems to be a constant characteristic of this extended haplotype in the Sardinian population and suggests that this and other extended haplotypes bearing C4 A or C4 B null alleles could be ancestral haplotypes which never duplicated at these loci.