RESUMO
Outcome of unrelated donor marrow transplantation is influenced by donor-recipient matching for HLA. Prior studies assessing the effects of mismatches at specific HLA loci have yielded conflicting results. The importance of high-resolution matching for all HLA loci has also not been established. We therefore examined the effects of HLA matching (low or high resolution or both) on engraftment, graft-versus-host disease (GVHD), and mortality in 1874 donor-recipient pairs retrospectively typed at high resolution for HLA-A, -B, -C, -DRB1, -DQ, and -DP. Mismatches at HLA-A, -B, -C, and -DRB1 each had similar adverse effects on mortality. Only HLA-A mismatches demonstrated significant adverse effects on GVHD. These adverse effects on outcome were more evident in transplants with low-resolution versus only high-resolution mismatches. Mismatches for HLA-DQ or -DP did not significantly affect outcome. When high-resolution mismatches at HLA-A, -B, -C, and -DRB1 were considered together, adverse effects on survival and GVHD were observed. We therefore conclude that matching for HLA-C should be incorporated into algorithms for unrelated donor selection. High-resolution mismatches at HLA-A, -B, -C, and -DRB1 adversely affect outcome, but less so than low-resolution mismatches. When clinical circumstances allow, high-resolution class I typing may help optimize donor selection and improve outcome.
Assuntos
Transplante de Medula Óssea/métodos , Antígenos HLA/química , Antígenos HLA-C/química , Teste de Histocompatibilidade , Adulto , Alelos , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Antígenos HLA-A/química , Antígenos HLA-B/química , Antígenos HLA-C/imunologia , Antígenos HLA-DP/química , Antígenos HLA-DQ/química , Antígenos HLA-DR/química , Cadeias HLA-DRB1 , Células-Tronco Hematopoéticas/imunologia , Histocompatibilidade , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Leucemia/terapia , Fatores de Tempo , Doadores de Tecidos , Resultado do TratamentoRESUMO
We tested the clinical reactions to a synthetic, Plasmodium falciparum, circumsporozoite multiple antigen peptide (MAP) vaccine in 39 volunteers immunized two to three times over 2-8 months using a dose escalation design. Immediate pain at the injection site was associated with the adjuvant QS-21 (P<0.001), and delayed local inflammatory reactions were associated with high-titered circulating IgG anti-MAP antibody (P=0.03). Because two volunteers developed acute, systemic urticaria after the third immunization associated with development of serum IgE MAP antibody, we employed immediate-type hypersensitivity skin tests (ITH-STs) using intradermal injections of diluted MAP vaccine to identify persons sensitized to the vaccine. ITH-STs were negative in seven volunteers tested 27 days after the first vaccination, but six of these individuals developed positive wheal and flare reactions when tested 14 or 83 days after the second vaccination; IgE MAP antibody was detected in only one of them. Another cohort of 16 volunteers, including the 2 allergic individuals, were ITH-ST negative when first tested late after their second or third vaccination at 6-7 months. Five of five non-immunized persons were also ITH-ST negative. ITH-STs may help identify individuals sensitized to malaria peptides and at potential risk of developing systemic allergic reactions after re-vaccination.
Assuntos
Antígenos de Protozoários/imunologia , Hipersensibilidade Tardia/induzido quimicamente , Vacinas Antimaláricas/efeitos adversos , Plasmodium falciparum/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adulto , Animais , Antígenos de Protozoários/biossíntese , Estudos de Coortes , Feminino , Experimentação Humana , Humanos , Hipersensibilidade/etiologia , Imunoglobulina E/biossíntese , Imunoglobulina G/biossíntese , Testes Intradérmicos , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/imunologia , Malária Falciparum/imunologia , Malária Falciparum/prevenção & controle , Masculino , Dor/induzido quimicamente , Dor/imunologia , Plasmodium falciparum/crescimento & desenvolvimento , Urticária/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/farmacologiaRESUMO
During the testing of the safety and immunogenicity of an adjuvanted, synthetic Plasmodium falciparum CS multiple antigen peptide (MAP) vaccine, we investigated the potential for using cutaneous delayed-type hypersensitivity (DTH) reactions as a correlate of immune response. We evaluated 27 of our volunteers for DTH reactions to intradermal inoculation (0.02 ml) of several concentrations of the MAP vaccine and adjuvant control solutions. Induration was measured 2 days after skin tests were applied. Nine of 14 vaccinees (64%) with serum, high-titered anti-MAP antibody developed positive DTH (>or=5mm induration), that first appeared by 29 days after immunization and persisted for at least 3-6 months after 1-2 more immunizations. In contrast, DTH responses were negative in eight of eight vaccinees with no or low antibody titers, and in five of five non-immunized volunteers. Biopsies of positive DTH skin test sites were histologically compatible with a DTH reaction. We conclude that the presence of T cell functional activity reflected by a positive DTH skin test response to the MAP antigen serves as another marker for vaccine immunogenicity.
