RESUMO
Purified hematopoietic stem cells (HSCs) were transplanted into NOD mice to test whether development of hyperglycemia could be prevented. Engraftment of major histocompatibility complex-mismatched HSCs was compared with bone marrow (BM) grafts. HSCs differed from BM because HSCs were more strongly resisted and HSC recipients retained significant levels of NOD T-cells, whereas BM recipients were full donor chimeras. Despite persistent NOD T-cells, all HSC chimeras were protected from hyperglycemia, and attenuation of islet lesions was observed. T-cell selection was altered in allogeneic HSC recipients as demonstrated by deletion of both donor and host superantigen-specific T-cells. Syngeneic and congenic hematopoietic cell transplants were also performed to differentiate the influence of the preparative regimen(s) versus the allografts. Unlike the allogeneic HSC transplantations, syngeneic or congenic grafts did not retard diabetes development. In a pilot study, overtly diabetic NOD mice were cured by co-transplantation of allogeneic HSCs and donor-matched islets. We conclude that allogeneic HSC transplants block allo- and autoimmunity, despite residual host T-cell presence. These data demonstrate for the first time that purified HSC grafts block development of autoimmune diabetes and illuminate how HSC grafts alter thymic and peripheral T-cell responses against auto- and alloantigens.
Assuntos
Diabetes Mellitus/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Camundongos Endogâmicos NOD/fisiologia , Animais , Diabetes Mellitus/etiologia , Diabetes Mellitus/genética , Ilhotas Pancreáticas/patologia , Transplante das Ilhotas Pancreáticas , Camundongos , Pancreatite/patologia , Pancreatite/cirurgia , Linfócitos T/fisiologia , Quimeras de Transplante , Transplante Homólogo , Transplante IsogênicoRESUMO
Within our field, improvement in fluorescence-activated cell sorting (FACS) and molecular technologies has led to various types of correlative studies that imply the developmental sequence and subsequent emigration of thymic-lymphocyte subsets. Unfortunately, the implied conclusions are often accepted unequivocally by most of the immunology community. In fact, direct demonstration of precursor progeny relationships by specific cell marking within the thymus, or specific delivery of purified cells at a particular stage of isolation back into the thymus, are the only methods that reproducibly identify cell stages and intermediates (1-11).
RESUMO
nu/nu mice fail to develop a thymus and mature T cells due to a defect in the whn gene encoding a transcription factor necessary for terminal epithelial cell differentiation. We investigated whether early T cell progenitor development in the nu/nu bone marrow is also defective. We demonstrated a maturation arrest of nu/nu marrow T cell progenitors associated with a lack of pTalpha gene expression and a failure to give rise to mature T cells in adoptive euthymic hosts. Wild-type hemopoietic stem cells rapidly matured into functional T cell progenitors in the marrow of euthymic or thymectomized but not nu/nu hosts. We show that defects in bone marrow prethymic T cell development can also contribute to T cell deficiency in nu/nu mice.
Assuntos
Células da Medula Óssea/imunologia , Células-Tronco Hematopoéticas/imunologia , Subpopulações de Linfócitos T/imunologia , Timo/imunologia , Transferência Adotiva , Animais , Apoptose/genética , Apoptose/imunologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Transplante de Medula Óssea , Antígenos CD2/biossíntese , Ciclo Celular/genética , Ciclo Celular/imunologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T/genética , Genes Codificadores da Cadeia alfa de Receptores de Linfócitos T , Marcadores Genéticos , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Imunofenotipagem , Injeções Intravenosas , Linfopenia/genética , Linfopenia/imunologia , Linfopenia/patologia , Masculino , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , RNA Mensageiro/biossíntese , Receptores de Antígenos de Linfócitos T alfa-beta , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Subpopulações de Linfócitos T/transplante , Antígenos Thy-1/biossíntese , Timo/metabolismo , Timo/patologia , Regulação para Cima/genética , Regulação para Cima/imunologiaRESUMO
The regulation of hematopoietic stem cell (HSC) homeostasis is not well understood. We screened for genetic polymorphisms that were linked to differences between mouse strains in the numbers of long-term reconstituting HSCs or restricted progenitors in the bone marrow. AKR/J mice had significantly higher frequencies and numbers of both HSCs and restricted progenitors in their bone marrow than C57BL/Ka-Thy-1.1 mice. The C57BL/Ka-Thy-1.1 alleles were partially dominant. A locus on chromosome 17, including the H-2 complex, was significantly linked to the frequency of long-term self-renewing HSCs but showed no evidence of linkage to the frequency of restricted progenitors. Conversely, a chromosome 1 locus exhibited suggestive linkage to restricted progenitor frequencies but was not linked to HSC frequency. This demonstrates that there are distinct genetic determinants of the frequencies of HSCs and restricted progenitors in vivo. The AKR/J chromosome 17 locus was not sufficient to increase HSC frequencies when bred onto a C57BL background. This suggests that to affect HSC frequencies, the product(s) of this locus likely depend on interactions with unlinked modifying loci.