RESUMEN
In subjects mismatched in the HLA alleles C*03:03/C*03:04 no allogeneic cytotoxic T-lymphocyte responses are detected in vitro. Hematopoietic stem cell transplantation (HSCT) with unrelated donors (UDs) showed no association between the HLA-C allele mismatches (CAMMs) and adverse outcomes; antigen mismatches at this and mismatches other HLA loci are deleterious. The absence of effect of the CAMM may have resulted from the predominance of the mismatch C*03:03/C*03:04. Patients with hematologic malignancies receiving UD HSCT matched in 8/8 and 7/8 HLA alleles were examined. Transplants mismatched in HLA-C antigens or mismatched in HLA-A, -B, or -DRB1 presented significant differences (P < .0001) in mortality (hazard ratio [HR] = 1.37, 1.30), disease-free survival (HR = 1.33, 1.27), treatment-related mortality (HR = 1.54, 1.54), and grade 3-4 acute graft-versus-host disease (HR = 1.49, 1.77) compared with the 8/8 group; transplants mismatched in other CAMMs had similar outcomes with HR ranging from 1.34 to 172 for these endpoints. The C*03:03/C*03:04 mismatched and the 8/8 matched groups had identical outcomes (HR ranging from 0.96-1.05). The previous finding that CAMMs do not associate with adverse outcomes is explained by the predominance (69%) of the mismatch C*03:03/03:04 in this group that is better tolerated than other HLA mismatches.
Asunto(s)
Enfermedad Injerto contra Huésped/epidemiología , Antígenos HLA-C/genética , Neoplasias Hematológicas/epidemiología , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Prueba de Histocompatibilidad/métodos , Adolescente , Adulto , Anciano , Algoritmos , Alelos , Niño , Preescolar , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/inmunología , Antígenos HLA-C/inmunología , Neoplasias Hematológicas/genética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Lactante , Persona de Mediana Edad , Análisis Multivariante , Prevalencia , Factores de Riesgo , Donante no Emparentado , Adulto JovenRESUMEN
HLA disparity has a negative impact on the outcomes of hematopoietic cell transplantation (HCT). We studied the independent impact of amino acid substitution (AAS) at peptide-binding positions 9, 99, 116, and 156, and killer immunoglobulin-like receptor binding position 77 of HLA-A, B, or C, on the risks for grade 3-4 acute graft-versus-host disease (GVHD), chronic GVHD, treatment-related mortality (TRM), relapse, and overall survival. In multivariate analysis, a mismatch at HLA-C position 116 was associated with increased risk for severe acute GVHD (hazard ratio [HR] = 1.45, 95% confidence interval [CI] = 1.15-1.82, P = .0016). Mismatch at HLA-C position 99 was associated with increased transplant-related mortality (HR = 1.37, 95% CI = 1.1-1.69, P = .0038). Mismatch at HLA-B position 9 was associated with increased chronic GVHD (HR = 2.28, 95% CI = 1.36-3.82, P = .0018). No AAS were significantly associated with outcome at HLA-A. Specific AAS pair combinations with a frequency >30 were tested for association with HCT outcomes. Cysteine to tyrosine substitution at position 99 of HLA-C was associated with increased TRM (HR = 1.78, 95% = CI 1.27-2.51, P = .0009). These results demonstrate that donor-recipient mismatch for certain peptide-binding residues of the HLA class I molecule is associated with increased risk for acute and chronic GVHD and death.
Asunto(s)
Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Enfermedad Aguda , Adolescente , Adulto , Anciano , Aloinjertos , Sustitución de Aminoácidos , Sitios de Unión/genética , Niño , Preescolar , Femenino , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/mortalidad , Antígenos HLA-C/química , Antígenos HLA-C/genética , Antígenos HLA-C/metabolismo , Trasplante de Células Madre Hematopoyéticas/mortalidad , Antígenos de Histocompatibilidad Clase I/química , Prueba de Histocompatibilidad , Humanos , Lactante , Masculino , Persona de Mediana Edad , Modelos Moleculares , Receptores KIR/metabolismo , Factores de Riesgo , Donantes de TejidosRESUMEN
Six young patients with X-linked agammaglobulinemia and proven mutations in Btk were treated with cord blood or bone marrow transplants from HLA-matched siblings. Complete blood counts, serum chemistries, serum immunoglobulin concentrations, lymphocyte cell surface markers, and physical findings were evaluated at 3- to 5-day intervals for the first 2 weeks after transplant and then every 3 to 6 months. The first three patients were not given any preparative regimen or antirejection drugs and at 24 to 42 months posttransplant these patients have shown no benefit or harm related to the transplants. The second three patients were not given a preparative regimen but were treated with cyclosporine A (70 days) and mycophenolate mophetil (28 days) after transplant. Two of these patients have developed normal sized, nontender cervical lymph nodes 3 to 12 months after transplant but none of the three patients have shown an increase in serum IgM or an increase in the number of peripheral blood B cells. It is likely that successful engraftment will require more aggressive immunosupressive medications.