Studies in B cell-deficient mice generated by continuous injection of anti-mu antibodies (muSM) showed that T cell priming in lymph nodes was dependent on antigen presentation by B cells. This concept has recently become controversial since a wide range, from complete deficiency to near normal T cell responses, was reported in studies carried out with B cell-deficient mice generated by gene disruption (muMT). In this study we show that in the absence of B cells, T cell responses are greatly reduced in all the available muMT mouse strains although responses in muMT of the C57BL/6 background (which were used for most studies with muMT) were much more variable and could reach up to 42% of control. In contrast, T cell responses in muMT --> F(1) bone marrow chimeras which have the same phenotype as muMT were totally impaired, suggesting a principle difference between mice developing without B cells (muMT mice) and muSM which are made B cell deficient only after birth. Normal T cell priming was completely restored by reconstitution of muMT and muMT --> F(1) mice with syngeneic B cells. Interestingly, only B cell populations containing antigen-specific B cells were capable of reconstituting T cell responses. Monoclonal B cells taken from Ig transgenic mice could not reconstitute responses to an irrelevant antigen. We also found that B cells were also required for systemic T cell priming when antigen concentrations were limiting but were not required for priming (for T cell help) when mice were immunized with a high antigen dose.
Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease of the central nervous system (CNS) that serves as a model for multiple sclerosis (MS) in humans. In mice, EAE is mediated by Th1 type CD4(+) T cells specific for various myelin proteins which migrate from the periphery to the CNS. Removal or blocking of CD4(+) cells before or shortly after disease induction was shown to prevent disease onset and/or disease progression but also results in general immune suppression. Most treatment regimens for autoimmune diseases currently rely on general suppression of the T-cell compartment most commonly by steroids. In this paper, an experimental, gene therapy-based model is presented in which susceptible mice are made resistant to EAE induction by specifically down-regulating an autoreactive T-cell population. By using a retroviral gene transfer protocol, normal B cells were genetically modified to constitutively express the SJL-specific proteolipid (PLP) encephalitogenic determinant and then adoptively transferred into syngeneic hosts. To ensure appropriate presentation of the exogenous encephalitogenic peptide in association with MHC class II, the encephalitogenic sequence was fused to a lysosomal targeting sequence. Adoptive transfer of syngeneic B cells expressing the PLP encephalitogenic determinant into normal, naive, genetically susceptible mice induced PLP-specific unresponsiveness and completely protected the majority (62% and 83% using an intermediate and a high titer retroviral vector, respectively) of the animals from EAE induction. The remaining animals had a delayed disease onset and/or lower disease severity. All protected mice expressed the exogenous gene in the spleen as detected by reverse transcriptase-polymerase chain reaction.
The current paradigm concerning the kinetics of hematopoiesis is that only the most primitive pluripotential bone marrow stem cells can support prolonged hematopoiesis whereas more differentiated, lineage-committed stem cells can only contribute to a particular lineage for a limited period of time. In this study, we present evidence that in mice, the spleen contains a long-lived myeloid-committed stem cell population(s) that continuously replenishes the mature myeloid lineage for at least 9 months. After myeloid-specific retroviral-mediated gene transfer, the exogenous gene could be detected in thioglycollate-induced macrophages and granulocytes by Southern blot analysis and by in situ polymerase chain reaction on an individual cell basis. The targeted stem cell population does not repopulate the bone marrow in secondary recipients and did not give rise to cells other than cells of the myeloid lineage. It therefore represents the first nonpluripotential stem cell population capable of replenishing a hemopoietic lineage for a long period of time. The ability to target a myeloid-specific stem cell could facilitate gene therapy of congenital disorders of the myeloid system such as lysosomal storage diseases. It also offers a unique opportunity to assess the immunologic consequences of expressing an exogenous gene of choice exclusively in the myeloid lineage. © 1998 by The American Society of Hematology.
The current paradigm concerning the kinetics of hematopoiesis is that only the most primitive pluripotential bone marrow stem cells can support prolonged hematopoiesis whereas more differentiated, lineage-committed stem cells can only contribute to a particular lineage for a limited period of time. In this study, we present evidence that in mice, the spleen contains a long-lived myeloid-committed stem cell population(s) that continuously replenishes the mature myeloid lineage for at least 9 months. After myeloid-specific retroviral-mediated gene transfer, the exogenous gene could be detected in thioglycollate-induced macrophages and granulocytes by Southern blot analysis and by in situ polymerase chain reaction on an individual cell basis. The targeted stem cell population does not repopulate the bone marrow in secondary recipients and did not give rise to cells other than cells of the myeloid lineage. It therefore represents the first nonpluripotential stem cell population capable of replenishing a hemopoietic lineage for a long period of time. The ability to target a myeloid-specific stem cell could facilitate gene therapy of congenital disorders of the myeloid system such as lysosomal storage diseases. It also offers a unique opportunity to assess the immunologic consequences of expressing an exogenous gene of choice exclusively in the myeloid lineage. © 1998 by The American Society of Hematology.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.