25th anniversary of the first successful allogeneic bone marrow transplants.
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Adult↗
Biomedical subjects
R A Good
Publications and source records attributed to R A Good.
Alteration of in vivo cytokine gene expression in mice infected with a molecular clone of the defective MAIDS virus.
The discovery of T helper type 1 (Th1) and T helper type 2 (Th2) phenotypes within the CD4+ T-lymphocyte population has allowed for further elucidation of the roles the T cells play in regulation of humoral and cellular immunity. It is suggested that differential activation of the CD4+ subsets, particularly up-regulation of the Th2 cell and down-regulation of the Th1 cell, may be associated with diseases as diverse as AIDS and asthma. We report herein that by using the polymerase chain reaction to analyze the kinetics of in vivo cytokine- and virus-specific gene expression, we can show that mice infected with the molecularly cloned MAIDS defective virus 1/27/A BM5 exhibit an alteration in cytokine gene expression that closely parallels an increase in spleen cell numbers, an increase in IgM production, a decrease in the stimulation index, and an increase in defective-virus gene expression in these mice. As has been suggested to be true for human AIDS, the observed alteration of cytokine gene expression suggests that a pattern of expression similar to that produced by Th2 cells may also have a role in the development of MAIDS.
Animals↗
Prevention and induction of occlusive coronary vascular disease in autoimmune (W/B)F1 mice by haploidentical bone marrow transplantation: possible role for anticardiolipin autoantibodies.
Male (NZW x BXSB)F1 (W/BF1) mice develop systemic autoimmunity involving autoantibodies, thrombocytopenia, lupus nephritis, and coronary vascular disease with myocardial infarction (CVD). To determine whether this murine lupus-associated CVD could be transferred to otherwise autoimmune-resistant (C57BL/6 x C3H/He)F1 (B6C3F1) mice via W/BF1 T-cell-depleted marrow (TCDM) transplants, or conversely whether the CVD of W/BF1 mice could be prevented by the reciprocal transplant, reciprocal haploidentical transplants of TCDM were performed. CVD developed only in mice with systemic autoimmunity. Mice that developed lupus had glomerulonephritis and thrombocytopenia and also had elevated titres of autoantibodies to double-strand DNA, cardiolipin, and platelets and elevated levels of circulating immune complexes. Of control W/BF1 mice, 80% developed lupus, and of these, 81% developed CVD with a mean grade of 2.5 +/- 0.8. Engraftment of W/BF1 mice with B6C3F1 marrow protected 90% of the recipients from the development of lupus, and none developed CVD. Engraftment of B6C3F1 mice with W/BF1 marrow induced lupus in 60% of the recipients, and of those, 33% developed CVD with a mean grade of 1.3 +/- 0.3. The B6C3F1 recipients of W/BF1 marrow which developed CVD had significantly higher titres of autoantibodies to cardiolipin (aCL; P < .01). These findings show that genetic abnormalities present in the W/BF1 hematopoietic stem cells contribute to autoantibody development, including aCL, and suggest that thrombogenic mechanisms induced by aCL may contribute to the development of CVD in this form of murine lupus erythematosus.
Animals↗
Production of minor lymphocyte stimulatory-1a antigen from activated CD4+ or CD8+ T cells.
Minor lymphocyte stimulatory (Mls) Ag are super Ag that stimulate a high proportion of T cells of a specific TCR V beta family. One of the super Ag, Mls-1a, which is recognized mainly by TCR V beta 6+ and V beta 8.1+ T cells, has recently been linked to the response to product of the open reading frame in 3'-long terminal repeat of endogenous mammary tumor virus, MTV-7. It is quite certain that B cells are able to produce and also to present the Mls-1a Ag. However, it remains to be determined whether other cell types, especially T cells, produce Mls-1a Ag. In this study using highly purified T cell subpopulations, capacity to produce Mls-1a Ag was analyzed by calculating the proportion of Mls-1a reactive V beta 6+ or V beta 8.1+ T cells in responding cell populations. We found that nonstimulated CD8+ T cells produced a low amount of Mls-1a Ag, and the capacity to do so was considerably increased by stimulation with immobilized anti-TCR mAb. By contrast, nonstimulated CD4+ T cells did not produce Mls-1a Ag at all. Even when CD4+ T cells were activated via TCR signaling with immobilized anti-TCR mAb, CD4+ T cells did not produce Mls-1a Ag. However, CD4+ T cells primed with conventional Ag in vivo produced Mls-1a Ag on restimulation with that specific Ag in vitro. These findings indicate that not only CD8+ T cells but also CD4+ T cells can produce Mls-1a Ag on appropriate stimulation, although different mechanisms for Mls-1a production may operate between the CD4+ and CD8+ T cells.
Amino Acid Sequence↗
Reconstitution of lymphoid tissues under the influence of a subclinical level of graft versus host reaction induced by bone marrow T cells or splenic T cell subsets.
Reconstitution of lymphoid tissues under the influence of subclinical graft versus host reaction (GVHR) has been investigated. Lethally irradiated AKR mice were reconstituted with B10 bone marrow (BM) cells which had been treated with anti-Thy-1 antibody alone without complement (GVHR chimera). Their immunological reconstitution was analyzed and compared with that of AKR recipients which had been reconstituted with B10 BM cells treated with anti-Thy-1 antibody plus complement (control chimera). One hundred percent of both chimeras survived more than 100 days without showing clinical signs of GVHR. However, full donor chimerism was accomplished at an early stage after reconstitution in the former GVHR chimeras, whereas a substantial number of recipient T cells persisted in control chimeras for the entire observation period. When reconstitution of various lymphoid tissues was compared between control and GVHR chimeras, no difference in the reconstitution of the thymus and spleen was noted. By contrast, the cellularity of peripheral lymph nodes in GVHR chimeras was regularly considerably lower than that of the control chimeras. The apparent insufficiency of lymph node reconstitution appeared to be attributable to the impairment of lymph node structure itself which may be involved in lymphocyte homing. Furthermore, clonal deletion of V beta 6+ T cells which are reactive to recipient (Mls-1a) antigens was abrogated in the GVHR chimeras but was normally induced in the more completely T cell-depleted control chimeras. This abrogation of clonal deletion of V beta 6+ T cells appeared to result from the early disappearance of recipient T cells in these chimeras. Thus, it appeared that donor T cells in the BM that survive anti-Thy-1 treatment in vitro plus subsequent BM transplantation induced a subclinical level GVHR which contributed to the full donor chimerism as well as abrogation of clonal elimination of V beta 6+ donor T cells. Indeed, inoculation of CD8+ T cells along with the transplantation of the T cell-depleted BM cells (anti-Thy-1 plus C-treated cells) from donor mice into the AKR recipients was also shown to induce a similar state in the recipients.
Animals↗
Diversification, not use, of the immunoglobulin VH gene repertoire is restricted in DiGeorge syndrome.
Immunoglobulin (Ig) genes were isolated from unamplified conventional as well as polymerase chain reaction-generated cDNA libraries constructed from the peripheral blood cells of a patient with complete DiGeorge syndrome. Comparison of the sequences of 36 heavy chain clones to the recently expanded database of human VH genes permitted identification of the germline VH genes that are expressed in this patient as well as placement of 19 of these genes in a partially resolved 0.8-mb region of the human VH locus. The pattern of VH gene use does not resemble the fetal (early) repertoire. However, as in the fetal repertoire, there are a number of cDNAs derived from germline genes that previously have been identified as autoantibodies. Two D mu sequences also were identified, as was another sequence resulting from a unique recombination event linking JH to an unidentified sequence containing a recombination signal sequence-like heptamer. All of the DiGeorge cDNAs are closely related to germline VH genes, showing little or no evidence of somatic mutation. In contrast, comparably selected IgM VH sequences derived from normal adult and age-matched human libraries, and from a second DiGeorge syndrome patient in whom the degree of thymic dysfunction is much less severe, exhibit considerable evidence of somatic mutation. The absence of somatic mutation is consistent with the atypical development of functional antibody responses associated with complete DiGeorge syndrome and implicates a role for T cells in the generation of diversity within the B cell repertoire.
Antibody Diversity↗
Transcriptional down-regulation of tumor necrosis factor-alpha gene expression by a synthetic peptide homologous to retroviral envelope protein.
We have previously shown that a synthetic peptide (CKS-17) homologous to retroviral envelope protein suppresses the accumulation of superantigen staphylococcal enterotoxin-induced TNF-alpha mRNA in human PBMC and in highly purified human monocytes. The present study was designed to examine the underlying mechanism(s) by which CKS-17 down-regulates the TNF-alpha mRNA expression using a human acute monocytic leukemia cell line THP-1 stimulated with the superantigen staphylococcal enterotoxin E. A cyclooxygenase inhibitor indomethacin does not reverse the inhibition of TNF-alpha mRNA expression by CKS-17, suggesting that prostaglandins are not responsible for the suppressive action of CKS-17. The inhibitory effect of CKS-17 is, however, significantly blocked by a protein synthesis inhibitor cycloheximide, indicating that CKS-17 requires de novo protein synthesis to induce the suppressive activity. The mRNA stability assays using actinomycin D show that CKS-17 does not decrease the TNF-alpha mRNA stability. Nuclear run-on transcription assays further reveal that CKS-17 suppresses the TNF-alpha mRNA transcription rate. Taken together, these results suggest that the synthetic retroviral peptide CKS-17 down-regulates TNF-alpha mRNA expression through inhibition of transcriptional activation of the TNF-alpha gene, which requires de novo synthesis of a transcriptional repressor protein(s).
Amino Acid Sequence↗
Development and characterization of monoclonal antiplatelet autoantibodies from autoimmune thrombocytopenic purpura-prone (NZW x BXSB)F1 mice.
Male (NZW x BXSB)F1 (W/BF1) mice develop systemic autoimmunity involving autoantibodies, progressive thrombocytopenia, lupus nephritis, and degenerative coronary vascular disease with myocardial infarction. Platelet-associated IgG (PAIgG) on the platelet surface mediates platelet destruction by the reticuloendothelial system in the autoimmune thrombocytopenic purpura (ATP) of W/BF1 mice. Because the epitopes targeted in ATP by PAIgG have not been identifiable using serum from thrombocytopenic W/BF1 mice, we developed seven hybridomas secreting antiplatelet monoclonal antibodies (MoAbs) using splenocytes of thrombocytopenic W/BF1 mice. Epitopes recognized by three MoAbs were similar to those recognized by PAIgG, because eluted IgG from platelets of thrombocytopenic W/BF1 mice inhibited platelet binding by MoAbs in competitive micro-enzyme-linked immunosorbent assay. Hybridoma cells or purified Ig from the ascites of two clones (2A12 and 6A6), when injected into nude mice produced acute thrombocytopenia, elevated the levels of PAIgG, purpura, and megakaryocytosis. MoAbs of two clones also reacted with single-stranded DNA or double-stranded DNA, and one of these clones (4-13) bound to cardiolipin (CL) but was nonpathogenic in nude mice, suggesting that anti-CL and antiplatelet autoantibodies can be distinct. On immunoblotting analysis, antiplatelet MoAbs frequently bound a 100-Kd platelet protein. These MoAbs contribute to an understanding of the etiopathogenesis of ATP and the several antigens and autoantibodies involved.
Animals↗
Lymphohemopoietic reconstitution using wheat germ agglutinin-positive hemopoietic stem cell transplantation within but not across the major histocompatibility antigen barriers.
Nonadherent (NA), low density (LD), wheat germ agglutinin-positive (WGA+) murine hemopoietic stem cell-enriched preparations (HSCPs) were tested for the capability to reconstitute lymphohemopoietic elements in lethally irradiated mice. HSCPs from BALB/c mice reconstituted lethally irradiated, major histocompatibility complex (MHC)-matched DBA/2 mice to normal histology of the thymus and spleen and normal humoral and cellular immune functions. By contrast, lethally irradiated B6 mice could not be reconstituted after transplantation with NA, LD, WGA+ cells from MHC-mismatched BALB/c mice. We previously observed frequent survival, stable chimerism, and normally vigorous functioning immune systems in B6 mice transplanted with T-cell-depleted bone marrow from both BALB/c and B6 donors. To extend these findings to a stem cell transplantation system, lethally irradiated B6 mice were transplanted with NA, LD, WGA+ cells from both BALB/c and B6 mice. These mixed stem cell-enriched preparations did not reconstitute the lethally irradiated, MHC-mismatched mice. By contrast, such HSCPs from BALB/c plus DBA/2 into DBA/2 mice reconstituted the hematologic and lymphoid tissues and functional immune systems when the donor and the recipient pairs were matched at MHC and mismatched at multiminor histocompatibility barriers. These purified blood progenitors thus appear to lack certain cells/factors essential for engraftment and reconstituting recipients in a fully allogeneic environment.
Animals↗
Lymphokine-activated killer cell activity of CD4-CD8- TCR alpha beta + thymocytes.
Functions of CD4-8-TCR alpha beta+ thymocytes, which are characterized by predominant usage of V beta 8.2 TCR, have remained unclear. In this study, we found that the CD4-8-TCR alpha beta + thymocytes expressed NK1.1 Ag and IL-2R beta-chain but not IL-2R alpha-chain. When the CD4-8- TCR alpha beta + thymocytes were cultured in the presence of IL-2, the CD4-8-TCR alpha beta + thymocytes vigorously proliferated. After 7 days of culture in the presence of 1000 U/ml of IL-2, approximately half of the CD4-8-TCR alpha beta + thymocytes lost NK1.1 Ag. However, the remaining half of the CD4-8-TCR alpha beta + cells showed increasing levels of NK1.1 Ag and acquired killer activity against tumor cells such as YAC-1, P815, and EL-4. These cells also killed syngeneic as well as allogeneic thymocytes. The LAK activity by the NK1.1+ CD4-8-TCR alpha beta + thymocytes was not inhibited by anti-NK1.1, anti-TCR alpha beta, or anti-CD44 mAb but was partially inhibited by anti-LFA-1 mAb. These findings indicate that the CD4-8-TCR alpha beta + thymocyte population can be divided into two population on the basis of NK1.1 expression after culture in the presence of IL-2. The NK1.1 Ag expression on the cultured CD4-8-TCR alpha beta + seems to be correlated to acquisition of LAK activity, although the NK1.1 Ag itself may not be directly involved in the target cell recognition. The present data suggest that the CD4-8- TCR alpha beta + thymocyte population is a functional T cell lineage which may serve as cells of immune defense and/or immune regulation.
Animals↗
Molecular basis of a multiple lymphokine deficiency in a patient with severe combined immunodeficiency.
We have previously reported that the T lymphocytes of a child with severe combined immunodeficiency are defective in the transcription of several lymphokine genes that include IL2, IL3, IL4, and IL5, which encode interleukins 2, 3, 4, and 5 (IL-2, -3, -4, and -5). To determine whether the defect in the patient's T lymphocytes involved a trans-acting factor common to the affected lymphokine genes, we examined the ability of nuclear factors from the patient's T lymphocytes to bind response elements present in the regulatory region of IL2. Nuclear factor NF-kB, activation protein 1 (AP-1), OCT-1, and NF-IL-2B binding activity were normal. In contrast, the binding of the nuclear factor of activated T cells (NF-AT) to its response element in the IL2 enhancer and to an NF-AT-like response element present in the IL4 enhancer was abnormal. To ascertain whether the abnormal NF-AT binding activity was related to an impaired function, we transfected patient and control T lymphocytes with constructs containing the reporter gene encoding chloramphenicol acetyl transferase (CAT) under the control of the entire IL2 regulatory region or of multimers of individual enhancer sequences. CAT expression directed by the IL2 regulatory region or by a multimer of the NF-AT-binding site was markedly lower in the patient relative to controls. In contrast, CAT gene expression directed by a multimer of the OCT-1 proximal (OCT-1p)-binding site was equivalent in patient and controls. These results indicate that an abnormality of/or influencing NF-AT may underlie the multiple lymphokine deficiency in this patient.
Cell Nucleus↗
Genetic selection for crescent formation yields mouse strain with rapidly progressive glomerulonephritis and small vessel vasculitis.
We have established a recombinant inbred strain of mouse named spontaneous crescentic glomerulonephritis-forming mouse/Kinjoh or SCG/Kj. Mice of this strain spontaneously develop rapidly progressive glomerulonephritis. This strain of mice was derived from (BXSB/Mp x MRL/Mp-lpr/lpr)F1 hybrid mice by brother x sister mating coupled with repeated histopathologic selection for breeding of mice whose parents had the highest frequency of crescent formation in the kidneys. In this strain of mice, nephritis appears earlier and is more rapidly progressive than in any other murine model of systemic lupus erythematosus. Histopathologically, the characteristic renal lesions in the mice of this strain express a most dramatic form of crescentic glomerulonephritis. The lesions in the kidneys show only slight fine granular immune deposits along the glomerular basement membrane associated with remarkable extraglomerular proliferation and hemorrhage in Bowman's space. Although selection was not based on vasculitis, mice of this strain also exhibit a high incidence of necrotizing vasculitis. These vascular lesions involve primarily small arteries and arterioles and many organs and tissues but spare the kidneys. Thus this form of vasculitis has been found to be correlated with the crescentic form of glomerulonephritis but not with lymphoid hyperplasia of the spleen. We conclude that, in this strain of mouse, the rapidly progressive glomerulonephritis is genetically restricted and that this genetic restriction is firmly linked to that responsible for the vasculitis.
Animals↗
Mixed chimerism and immunologic tolerance.
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Amylopectin↗
Calories, parity, and prolactin influence mammary epithelial kinetics and differentiation and alter mouse mammary tumor risk.
Reduced calorie intake (RCI) suppresses mouse mammary tumor virus (MMTV) transcription and reduces mammary tumor (MT) incidence in C3H/Ou mice. Since efficient retroviral expression requires cell division, we investigated whether the suppression of MMTV and MT by RCI reflects changes in mammary histogenesis and lowered epithelial kinetics. Prolactin (PRL) augments MMTV transcription. Since PRL levels may be lowered by RCI, we evaluated whether lowered PRL in ad libitum-fed mice alters mammary histogenesis and MT incidence in a manner comparable to RCI. Pregnancy augments MMTV transcription. Hence, we also determined the effect of parity on mammary histogenesis, kinetics, and MT risk. One hundred thirty-five C3H/Ou mice were fed ad libitum or a RCI level and separated into six experimental groups. Twenty ad libitum-fed mice were injected with a dopaminomimetic to lower PRL, and 20 RCI mice were engrafted with adenohypophyses to elevate PRL. Twenty-seven ad libitum-fed mice and twenty-eight RCI mice experienced a single parturition. RCI protected nulliparous (P = 0.0001) and parous mice (P = 0.005) from MT development. Reduced calories or lowered PRL with ad libitum feeding similarly influenced mammary histogenesis, kinetics and MT risk (P > 0.5). Mammary glands of RCI mice or of ad libitum-fed mice with lowered PRL were histologically comparable and principally ductular with a low DNA-labeling index (DNA-LI) (P < 0.001). In contrast, the parenchyma of ad libitum-fed mice or of RCI mice with elevated PRL had exuberant alveoli formation, an elevated DNA-LI (P < 0.001), and preneoplastic lesions. Parity did not change the elevated DNA-LI and MT risk of ad libitum-fed mice but increased the mammary DNA-LI (P < 0.001) and MT incidence (P = 0.01) of RCI mice. Prevention of mammary tumorigenesis in C3H/Ou mice by RCI may result from modulated serum PRL activity and reduced mammary epithelial kinetics which suppress MMTV transcription and minimize the risk of activating protooncogenes.
Animals↗
NK1.1+ CD4+ CD8- thymocytes with specific lymphokine secretion.
CD4+8- or CD4-8+ thymocytes have been regarded as direct progenitors of peripheral T cells. However, recently, we have found a novel NK1.1+ subpopulation with skewed T cell antigen receptor (TcR) V beta family among heat-stable antigen negative (HSA-) CD4+8- thymocytes. In the present study, we show that these NK1.1+ CD4+8- thymocytes, which represent a different lineage from the major NK1.1- CD4+8- thymocytes or CD4+ lymph node T cells, vigorously secrete interleukin (IL)-4 and interferon (IFN)-gamma upon stimulation with immobilized anti-TcR-alpha beta antibody. On the other hand, neither NK1.1- CD4+8- thymocytes nor CD4+ lymph node T cells produced substantial amounts of these lymphokines. A similar pattern of lymphokine secretion was observed with the NK1.1+ CD4+T cells obtained from bone marrow. The present findings elucidate the recent observations that HSA- CD4+8- thymocytes secrete a variety of lymphokines including IFN-gamma, IL-4, IL-5 and IL-10 before the CD4+8- thymocytes are exported from thymus. Our evidence indicates that NK1.1+ CD4+8- thymocytes are totally responsible for the specific lymphokine secretions observed in the HSA- CD4+8- thymocytes.
Animals↗
Development of T cells in SCID mice grafted with fetal thymus from AKR mice or F344 rats.
To examine the development of T cells within an allogeneic or xenogeneic environment, we engrafted the fetal thymus from AKR mice or F344 rats under the kidney capsule of SCID mice (mTG and rTG mice). T lymphopoiesis developed in SCID mice 2 months after transplantation, although the ratio of CD4/CD8 in both experimental groups was different from that of normal control. T cells in mTG mice did not show in vitro proliferation or cytotoxicity against either host-type C.B-17 (H-2d) or donor-type AKR (H-2k) cells, while they exerted potent activities against third-party B10 (H-2b) cells. In contrast, T cells in rTG mice exhibited proliferation against both host-type C.B-17 and donor-type F344 rat cells. Consistently, graft-vs.-host disease symptoms developed in these mice and histological examination showed impressive infiltration of lymphocytes into the skin or into the mucosal layers of the stomach. Activated state of T cells in rTG mice was also evidence by the positive expression of interleukin-2 receptor. Taken together, fetal thymus appears to contain progenitor cells which are sufficient for in vivo reconstitution of T lymphopoiesis, but species-specific environment is important for the induction of tolerance. In mTG mice, V beta 6+ T cells reactive to donor Mlsa determinants and V beta 3+ T cells reactive to host Mlsc determinants were deleted, suggesting that tolerance was regulated mainly by clonal deletion. By contrast, V beta 11+ T cells reactive to Mlsf determinants were not deleted possibly due to the lack of their ligands.
Animals↗
Interleukin-1-dependent mitogenic responses induced by protoscoleces of Echinococcus multilocularis in murine lymphocytes.
Mitogenic effects of protoscoleces (PSCs) of Echinococcus multilocularis on murine lymphocytes were studied. Spleen cells from normal BALB/c mice showed significant proliferative responses when cocultured with PSCs. Proliferative responses were observed in both the T and B cell populations. The PSCs also stimulated cells of the macrophage/monocyte lineage to secrete interleukin-1 (IL-1). Depletion of plastic- and Sephadex G-10-adherent cells from the spleen cell population significantly reduced the proliferative responses to PSCs and the low responsiveness was restored by addition of plastic-adherent cells to these cultures. Furthermore, addition of anti-IL-1 serum to the spleen cell cultures stimulated with PSCs completely suppressed the proliferative responses. These findings demonstrate that the mitogenic effect of PSC on lymphocytes depends on IL-1 secreted by cells of macrophage/monocyte lineage.
Animals↗
Prolactin acts on the extreme 5' portion of MMTV LTR involving a mammary cell-specific enhancer.
We have previously shown that a human mammotropic polypeptide hormone, prolactin (PRL) can act synergistically with steroid hormones to regulate gene expression directed by the long terminal repeat of mouse mammary tumor virus (MMTV LTR) in a human ductal carcinoma cell line T47D cells using a chloramphenicol acetyltransferase reporter gene system and gene transfection methods. In the present study, using various recombinant plasmids we analyzed functional elements in the MMTV LTR that is essential for the PRL responses. We show that the PRL-responsive elements are located in the extreme 5' end of the MMTV LTR, a region previously described by others to be a mammary cell-specific enhancer.
Breast↗