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W S Lapp

Publications and source records attributed to W S Lapp.

At least 19 recordsLinked to original sources
PubMed2000

Activation of macrophage cytostatic effector mechanisms during acute graft-versus-host disease: release of intracellular iron and nitric oxide-mediated cytostasis.

During acute graft-versus-host disease (GVHD) the activation of macrophages (Mphi) is mediated by 2 signals, interferon (IFN)-gamma and bacteria-derived lipopolysaccharide (LPS). A cascade of inflammatory responses that includes the release of mediators of tissue injury follows Mphi activation. Among the tissues characteristically targeted during acute GVHD are epithelial tissues of the skin and gastrointestinal tract that normally undergo continuous proliferation and are therefore sensitive to cytostatic processes. We have investigated whether Mphi can mediate cytostatic mechanisms capable of interrupting cell proliferation during acute GVHD. GVHD was induced in nonirradiated C57BL/6XAF(1) (B6AF(1)) mice by the injection of 60 x 10(6) (acute GVHD) or 30 x 10(6) (nonlethal GVHD) C57BL/6 (B6) lymphoid cells. Mphi from animals undergoing acute GVHD could be triggered by normally insignificant quantities of LPS to mediate a cytostatic effect on target cells, resulting in the complete shutdown of cellular proliferation. The same amounts of LPS had no effect on Mphi from normal or syngeneically transplanted animals. Mphi mediated the release of significant quantities of intracellular iron from target cells undergoing cytostasis. Reversal of cytostasis occurred following inhibition of nitric oxide (NO) production by N(G)-monomethyl-L-arginine (NMMA). Production of NO by LPS-triggered Mphi reflected the severity of GVHD. NO release increased significantly during acute GVHD but was only transiently increased during nonlethal GVHD. The results provide evidence that, as a result of activation during acute GVHD, Mphi produce NO and induce the release of iron from target cells, resulting in a potent cytostatic effect that inhibits cellular proliferation. (Blood. 2000;96:1836-1843)

Acute Disease↗
PubMed2000

The T-cell protein tyrosine phosphatase.

In recent years, the T-cell protein tyrosine phosphatase (TC-PTP) has become an important member of the protein-tyrosine phosphatase (PTP) family in two aspects. Firstly, TC-PTP has been reported to act on downstream signalling events initiated by the epidermal growth receptor, suggesting that it may act as an important modulator of receptor tyrosine kinases and mitogenic signalling. Secondly, the finding of immune deficiency and lethality observed in TC-PTP null mice emphasizes the importance of this small PTP in the hematopoietic system. In this review, we provide a summary of the recent literature published on the TC-PTP and its various orthologs. Although much remains to be uncovered, some recent findings on the function of this small PTP suggest that it plays a critical role in regulating mammalian cell signalling.

Amino Acid Sequence↗
PubMed1997

Role of interferon-gamma in the priming of decidual macrophages for nitric oxide production and early pregnancy loss.

We have previously shown that both priming and triggering signals were needed for nitric oxide production by decidual macrophages and that nitric oxide was responsible for embryo wastage. In this study, we investigated the role of IFN-gamma as the primary signal for macrophage activation in early embryo loss. IFN-gamma-deficient (GKO) and heterozygous F1 control mice were injected with lipopolysaccharide (LPS) at day 7 of gestation. The results showed that the GKO mice were more resistant to LPS-induced embryo loss than the wild type. This suggested that IFN-gamma was needed for LPS-induced embryo resorption and that decidual macrophages from pregnant GKO mice were not primed and could not be activated when given LPS. Further, the results showed that IFN-gamma mRNA was simultaneously expressed in the same embryos that also expressed mRNA markers for macrophage activation (TNF-alpha and iNOS), indicating that macrophage activation could be a consequence of IFN-gamma production. Similarly, we investigated the role of IL-12 as a switch cytokine capable of eliciting TH1-associated cytokine production including IFN-gamma. The results showed that IL-12 mRNA expression was correlated with IFN-gamma expression and macrophage activation. In this in vivo study, we showed for the first time that spontaneously increased decidual IFN-gamma expression is detrimental to embryo survival.

Animals↗
PubMed1997

Impaired bone marrow microenvironment and immune function in T cell protein tyrosine phosphatase-deficient mice.

The T cell protein tyrosine phosphatase (TC-PTP) is one of the most abundant mammalian tyrosine phosphatases in hematopoietic cells; however, its role in hematopoietic cell function remains unknown. In this report, we investigated the physiological function(s) of TC-PTP by generating TC-PTP-deficient mutant mice. The three genotypes (+/+, +/-, -/-) showed mendelian segregation at birth (1:2:1) demonstrating that the absence of TC-PTP was not lethal in utero, but all homozygous mutant mice died by 3-5 wk of age, displaying runting, splenomegaly, and lymphadenopathy. Homozygous mice exhibited specific defects in bone marrow (BM), B cell lymphopoiesis, and erythropoiesis, as well as impaired T and B cell functions. However, myeloid and macrophage development in the BM and T cell development in the thymus were not significantly affected. BM transplantation experiments showed that hematopoietic failure in TC-PTP -/- animals was not due to a stem cell defect, but rather to a stromal cell deficiency. This study demonstrates that TC-PTP plays a significant role in both hematopoiesis and immune function.

Animals↗
PubMed1997

Early embryo loss is associated with the prior expression of macrophage activation markers in the decidua.

In early embryo loss, the activation of maternal immune effector mechanisms play a critical role in determining the success or failure of a pregnancy. We have previously shown that increased nitric oxide production by decidual macrophages is involved in early embryo loss occurring at day 12 of gestation. In this study, using reverse transcription-PCR and Southern blotting, the expression of inducible nitric oxide synthases (iNOS) and TNF-alpha mRNA was determined to quantify macrophage activation in individual murine embryos in a model of spontaneous early embryo loss. At day 8 of gestation, 32 and 29% of embryos with no apparent pathology showed an increase in iNOS and TNF-alpha mRNA expression, respectively. This corresponds to the natural resorption rate seen in the mouse model. In addition, the percentage of embryos with increased iNOS and TNF-alpha mRNA expression was further augmented when pregnant mice were induced to abort at a higher rate. These results showed, for the first time, a correlation between increased iNOS and TNF-alpha expression and embryo resorption. The results provide evidence for the presence of activated macrophages at implantation sites before overt embryo damage occurs.

Animals↗
PubMed1997

Progressive accumulation of bacterial lipopolysaccharide in vivo during murine acute graft-versus-host disease.

In a previous report the authors demonstrated that acute graft-versus-host disease (GVHD) was associated with pathologic amounts of tumour necrosis factor alpha (TNF-alpha) and the appearance of lipopolysaccharide (LPS) in the blood of GVH reactive mice just prior to death. In this study the authors have investigated the kinetics of LPS accumulation in different organs during the course of acute GVHD using a murine model. Unirradiated C57BL/6 x AF1 (B6AF(1)) mice were transplanted with C57BL/6 (B6) lymphoid cells and killed at predetermined times after transplantation for LPS analysis. Control animals were injected with either 60 x 10(6) B6AF1 lymphoid cells (syngeneic) or 60 x 10(6) irradiated (2000 rad) CBA lymphoid cells (allogeneic). Lipopolysaccharide began to appear in the liver and the spleen of GVH reactive mice from day 2 post-transplant and by day 10 all GVH reactive mice tested positive for hepatic and splenic LPS. Low levels of LPS were detected in some control mice from days 2 to 10 post-transplant but LPS was never detected after day 10 in control groups. Total hepatic and splenic LPS in acute GVH reactive mice peaked at a time coincident with the appearance of LPS in the serum and with the onset of mortality. These results demonstrate that tissue levels of LPS increase throughout the course of acute GVHD and are sufficient to trigger the release of pathologic amounts of TNF-alpha from primed macrophages resulting in the cachexia and mortality associated with acute GVHD in this model.

Acute Disease↗
PubMed1996

IL-12 p40 messenger RNA expression in target organs during acute graft-versus-host disease. Possible involvement of IFN-gamma.

The onset of acute graft-vs-host disease (aGVHD) is accompanied by macrophage (M phi) priming and the presence of bacteria-derived LPS in the sera of transplanted animals. Priming of M phi occurs during aGVHD despite the suppression of T cell function. We have investigated whether IL-12 mediates the continued production of IFN-gamma during the state of T cell immunosuppression that accompanies aGVHD. Acute GVHD was induced in nonirradiated AxC57BL/6F1 mice by the injection of C57BL/6 lymphoid cells. Despite T cell immunosuppression, M phi became primed, as shown by their expression of inducible nitric oxide synthase mRNA and their production of nitric oxide in response to LPS. Continual exposure to IFN-gamma was required to maintain a primed state in M phi during aGVHD. IL-12 p40 peptide mRNA was increased in M phi purified from animals undergoing aGVHD 14 days after transplantation. Target organs of aGVHD, including thymus, salivary gland, and lung, showed increased IFN-gamma mRNA between days 7 and 14 after transplantation. The increase was accompanied by an induction of mRNA for the p40 peptide of IL-12 and inducible nitric oxide synthase within the target organs. These results provide evidence for localized production of IFN-gamma within aGVHD target organs and suggest that it is mediated by LPS-induced production of IL-12 by M phi. Our data elucidate the mechanism of activation of M phi during aGVHD that results in TNF-alpha and nitric oxide production and delineates the effector role of M phi in the pathology of aGVHD.

Acute Disease↗
PubMed1996

The role of endogenous glucocorticoids on host T cell populations in the peripheral lymphoid organs of mice with graft-versus-host disease.

Previously, we demonstrated that immature CD4+8+ and mature CD4+ thymocyte populations were selectively eliminated during murine graft-versus-host disease (GVHD) as a consequence of elevated levels of endogenous glucocorticoids. In this report, we investigated whether the marked reduction of CD4+8+ and CD4+ thymocyte populations would affect host CD4+ and CD8+ T cell populations in the spleens and lymph nodes (LN) of mice undergoing GVHD. GVHD was induced in (C57BL/6 x A)F1 (B6AF1) mice by injecting A strain parental lymphoid cells. Using an antibody against H2Kb antigens, labeled host B6AF1 cells were distinguished from unlabeled donor A cells. Our results demonstrated a marked deficiency of host CD4+ and CD8+ T cells in the spleens and LN of GVHD mice on day 21 after GVHD induction. The severe reduction of host T cell populations in the peripheral lymphoid organs did not appear to result from the elimination of CD4+8+ and CD4+ thymocyte populations. However, adrenalectomy before GVHD induction reversed the severe loss of both host CD4+ and CD8+ T cell populations in the LN of GVHD mice on day 21, whereas cortisone treatment of adrenalectomized (ADX) GVHD mice resulted in reduction of host LN CD4+ and CD8+ T cell populations similar to that observed in non-ADX GVHD animals on day 21. In addition, adrenalectomy markedly improved the proliferative response of LN T cells to mitogens when compared with immunosuppressed T cells from the LN of non-ADX GVHD mice. In contrast, adrenalectomy did not reverse splenic T cell immunosuppression and the marked reduction of splenic host T cell populations during GVHD. These results suggest that high levels of endogenous glucocorticoids during GVHD play a central role in mediating severe deficiency of host T cell populations and inducing severe T cell immunosuppression in the LN, but not in the spleen, of GVHD mice.

Adrenalectomy↗
PubMed1995

Induction of a glucocorticoid-sensitive F1-anti-parental mechanism that affects engraftment during graft-versus-host disease.

Studies have shown that graft-vs-host disease (GVHD) in animal models induces persistent elevated levels of circulating adrenal glucocorticoids. In this report, we investigated the effects of endogenous glucocorticoids on the outcome of GVHD by adrenalectomizing (ADX) unirradiated (C57BL/6 x A)F1 (B6AF1) mice before GVHD induction. GVHD was induced by injection of 20 x 10(6) A strain parental lymphoid cells into B6AF1 mice. Our results demonstrated that non-ADX recipient mice experienced features characteristic of GVHD on day 13, which became progressively more severe by days 18 to 21. The GVHD features included severe immunosuppression, reversal in the host splenic CD4+/CD8+ ratio, histopathologic lesions in different tissues, and high parental cell chimerism in the spleens and lymph nodes. In contrast, ADX F1 recipient mice experienced GVHD features on day 13 similar to their non-ADX counterparts; however, ADX animals recovered rapidly from GVHD by days 18 to 21. Flow cytometry showed that, although a relatively high frequency of parental cells was detected in the spleens and lymph nodes of ADX mice on day 13, nearly all of the parental cells in the peripheral lymphoid organs disappeared on days 18 to 21, the time of recovery from GVHD. The marked reduction of parental cells and recovery from GVHD were prevented by treating ADX F1 mice with either exogenous glucocorticoid, anti-asialoGM1, or anti-CD8, but not anti-NK1.1 Ab. These results suggest that a dramatic recovery from GVHD was induced by a cell-mediated, steroid-sensitive F1-anti-parental mechanism. The F1-anti-parental phenomenon described herein is different from classical hybrid resistance.

Adrenalectomy↗
PubMed1995

Levels of p56lck and p59fyn are reduced by a glucocorticoid-dependent mechanism in graft-versus-host reaction-induced T cell anergy.

The graft-versus-host reaction (GVHR) results in profound, long-lasting immunosuppression characterized by T cell unresponsiveness to antigenic and mitogenic stimuli. In this report, the roles of the protein tyrosine kinases p56lck and p59fyn in GVHR-induced T cell anergy were investigated. GVHR was induced by the intravenous transfer of parental lymphoid cells into F1 hybrid recipient mice. The levels of lck and fyn declined dramatically in splenic and lymph node T cells of mice undergoing GVHR as the reaction progressed and T cell immunosuppression developed. Adrenalectomy of the GVH-reactive mice prevented both the GVHR-induced reduction of lck and fyn and the long-term T cell unresponsiveness to mitogens, suggesting a glucocorticoid-mediated mechanism. Indeed, treatment with exogenous glucocorticoids induced lck and fyn down-regulation in the lymph node T cells of normal mice, and in cultured T cell clones. We propose that the increase in endogenous glucocorticoids during GVHR triggers a reduction in T cell lck and fyn, leading to the severe immunosuppression of GVHR; this may represent a general mechanism of glucocorticoid-mediated immune regulation.

Adrenalectomy↗
PubMed1995

Increased expression of proopiomelanocortin (POMC) mRNA in adrenal glands of mice undergoing graft-versus-host disease (GVHD): association with persistent elevated plasma corticosterone levels.

GVHD in animal models induces severe thymic atrophy as a result of prolonged secretion of high concentrations of adrenal glucocorticoids. In this study we investigated the mechanism responsible for the persistent stimulation of the adrenal glands to secrete glucocorticoids in mice undergoing GVHD. GVHD was induced across the major and multiple minor histocompatibility antigen difference in unirradiated C57Bl/6 x AF1 hybrid mice by the intravenous injection of A strain parental lymphoid cells. Our results showed plasma corticosterone (CS) levels were elevated in association with high concentrations of corticotropin (ACTH) in both the GVHD and control syngeneic (SYN) groups on day 9. By days 16 and 24, plasma CS and ACTH in the SYN mice returned to basal levels. In contrast, plasma CS levels remained elevated in the GVHD animals on days 16 and 24 despite decreasing concentrations of plasma ACTH. Reverse transcription-polymerase chain reaction (RT-PCR) showed several-fold increase in POMC mRNA in the adrenal glands of GVHD mice compared with SYN animals. In addition, high mRNA levels for murine prohormone convertase 1, the enzyme that cleaves POMC into ACTH, were also detected in GVHD adrenals. Histological analysis of GVHD adrenals failed to show any sign of adrenalitis, and RT-PCR of GVHD adrenals also failed to detect mRNA for interferon-gamma (IFN-gamma), a cytokine expressed by activated T and natural killer (NK) cells. However, mRNA for IL-12, a cytokine produced by activated macrophages, was increased in GVHD adrenals, suggesting that resident adrenal macrophages were activated during GVHD. Our findings suggest that persistent elevated levels of plasma glucocorticoids during GVHD could be mediated by intra-adrenal ACTH produced by resident adrenal macrophages activated as a consequence of GVHD.

Adrenal Glands↗
PubMed1994

A donor-derived asialo-GM1+ cell induces depression of B-cell genesis during systemic graft-versus-host disease.

The nature of the effector cell(s) responsible for the depression of B-cell genesis in the bone marrow of mice undergoing systemic graft-versus-host disease (GVHD) has been examined. Donor C57BL/6 (B6) mice were treated in vivo with either a single injection of anti-asialo GM1 antibody (anti-ASGM1) to eliminate naturally occurring (endogenous) ASGM1+ cells or B6xAF1 (B6AF1) lymphoid cells followed by anti-ASGM1 to eliminate both endogenous and "induced" ASGM1+ cells. Lymphoid cells from donor mice after the elimination of endogenous ASGM1+ cells produced severe GVHD and concomitant depression of B-cell genesis when injected into B6AF1 recipients. In contrast, cells from donors depleted of both the endogenous and inducible ASGM1+ populations did not cause GVHD or depletion of B lineage cells in B6AF1 recipients but did depress B-cell genesis in B6C3F1 mice. The "induced" ASGM1+ cells were Thy 1+, but their elimination did not significantly alter either overall T-cell function or specific cytotoxic T-cell (CTL) reactivity against the sensitizing (B6AF1) strain. The results suggest that the effector cell responsible for the depression of B-cell genesis during systemic GVHD can be induced to express ASGM1, is strain-specific and Thy 1+; but is not a conventional CTL.

Animals↗
PubMed1994

Irradiation of the skin and systemic graft-versus-host disease synergize to produce cutaneous lesions.

In this report, the relationship between irradiation and graft-versus-host disease (GVHD)-induced cutaneous injury was investigated. Unirradiated F1 hybrid mice were grafted with irradiated skin and then injected with parental strain lymphoid cells to induce GVHD. Although low grade dermal lymphoid infiltrates were observed in unirradiated skin grafts of some GVH-reactive mice, and irradiated grafts of normal animals showed occasional fibrosis, only the irradiated grafts of GVH-reactive mice developed lesions consisting of vacuolar degeneration of the epidermal-dermal junction and necrotic keratinocytes accompanied by pronounced epidermal infiltrates, characteristic of clinical cutaneous GVHD. The results suggest that cutaneous irradiation exerts a permissive effect on lesion formation in the skin of mice undergoing GVHD. Furthermore, systemic irradiation, known to exacerbate the severity of GVHD, is not required. Cutaneous lesions may be triggered by radiation injury of keratinocytes, up-regulation of adhesion molecules on irradiated endothelium, destruction of protective radiosensitive intraepithelial lymphocytes, and radiation-induced priming of intradermal macrophages.

Animals↗
PubMed1993

Thymic selection and thymic major histocompatibility complex class II expression are abnormal in mice undergoing graft-versus-host reactions.

The graft-vs.-host reaction (GVHR) results in damage to the epithelial and lymphoid compartments of the thymus and thus in abnormal maturation and function of thymocytes in mice undergoing GVHR. In this report, the effects of GVHR on thymic T cell receptor (TCR) expression and usage have been investigated. GVHR was induced in unirradiated F1 hybrid mice by the intravenous transfer of parental lymphoid cells. Expression of the CD3/TCR complex on thymocyte subsets defined by CD4 and CD8 was studied by three-color flow cytometry. The level of CD3/TCR was decreased on CD4+CD8-, but not CD4-CD8+, mature thymocytes. The lack of upregulation of CD3/TCR on CD4 single-positive thymocytes, but not on their CD8+ counterparts, suggested an abnormality of class II major histocompatibility complex (MHC) expression in the thymuses of mice undergoing GVHR. Immunofluorescence staining of thymic frozen sections revealed that MHC class II expression was dramatically decreased in GVH-reactive mice. GVHR-induced changes in positive and negative selection were evaluated by determining the incidence of specific V beta TCR segment usage in the thymus. In normal mice, thymocyte usage of any given V beta segment was highly consistent between individuals of the same strain and age; however, a marked divergence in the incidence of TCR V beta 6hi and V beta 8hi cells between GVH-reactive littermate mice was observed, suggesting that thymic positive selection had become disregulated in these animals. Furthermore, negative selection was defective; the incidence of phenotypically self-reactive V beta 6hi T cells was significantly greater in the thymuses of GVH-reactive mice bearing the endogenous superantigen Mls-1a than in untreated controls. Thus, mice undergoing GVHR showed defective TCR upregulation on CD4+CD8- thymocytes and changes in TCR usage reflecting aberrant thymic selection, in conjunction with decreased expression of MHC class II. Most abnormalities of TCR expression and usage on CD4+ thymocytes observed in GVH-reactive mice were analogous to those of class II knockout mice.

Acute Disease↗
PubMed1992

Macrophage priming and lipopolysaccharide-triggered release of tumor necrosis factor alpha during graft-versus-host disease.

In this report we have investigated macrophage (M phi) activity and tumor necrosis factor alpha (TNF-alpha) production during graft-vs.-host disease (GVHD). TNF-alpha production by M phi requires two signals: priming of M phi by interferon followed by triggering of TNF-alpha production and release by lipopolysaccharide (LPS). The state of M phi activation was examined in nonirradiated B6AF1 recipient mice injected with either 60 x 10(6) (acute GVHD) or 30 x 10(6) (nonlethal GVHD) parental B6 lymphoid cells. During the early phase of acute GVHD, administration of normally sublethal amounts of LPS-triggered release of significant amounts of TNF-alpha into the serum resulting in death of the animals within 36 h. Normal animals treated with the same dose of LPS neither died nor produced detectable amounts of serum TNF-alpha. In vitro studies demonstrated that M phi were primed during GVHD. The level of M phi priming was greater during acute GVHD than nonlethal GVHD since 100-fold less LPS was required to trigger killing of a TNF-alpha-sensitive cell line by M phi from acute GVHD animals. The amount of TNF-alpha released into the serum after LPS injection increased during the course of the GVHD and was significantly greater in acute GVH-reactive mice. Endogenous LPS was detected in the serum of acute GVH-reactive animals coincident with the onset of mortality. The data provide evidence that during GVHD M phi are primed as a result of the allogeneic reaction and that endogenous LPS therefore triggers M phi production of TNF-alpha resulting in the symptoms characteristic of acute GVHD.

Animals↗
PubMed1991

T cell subsets in the thymus of graft-versus-host immunosuppressed mice. Sensitivity of the L3T4+Lyt-2- subset to cortisone.

We have investigated the effects of graft-versus-host disease on T cell differentiation in the murine thymus. We previously reported that GVH-induced thymic dysplasia results in a T cell immunodeficiency associated with a lack of IL-2 production. This deficiency in IL-2 production may be the result of a reduction in the number of L3T4+Lyt-2- IL-2-producing cells or of a functional defect in this population. To test these two alternatives, flow cytometry analysis of L3T4 and Lyt-2 antigen expression on thymocytes along with immunofluorescence microscopy were employed to assess T cell phenotypes in thymuses of GVH mice. GVH reactions were induced by injecting 40 x 10(6) C57BL/6 (B6) or A strain lymphoid cells into C57BL/6xAF1 (B6AF1) mice. Thymocyte populations were quantitated on different days after GVH induction. In the normal thymus, the ratio of L3T4/Lyt-2 single positive cells was greater than 2:1. In contrast, such a ratio was less than 1:1 in the atrophic GVH thymus, owing to a selective reduction in the number of L3T4+Lyt-2- cells. Following cortisone treatment the ratio of L3T4/Lyt-2 single positive thymocytes in normal F1 mice was approximately 3:1, whereas in GVH animals this ratio was reversed (1:2). This reversal was due to a selective reduction in the absolute numbers of L3T4+Lyt-2- cells. In adrenalectomized GVH animals, thymic cortical atrophy was prevented and normal ratios of L3T4/Lyt-2 single positive cells were observed. However, when these animals were treated with cortisone, the L3+T4/Lyt-2- population was more sensitive than was the L3T4- Lyt2+ population, thereby resulting in a 1:2 L3T4/Lyt-2 ratio. These results demonstrate that single positive L3T4 cells are present in the murine GVH thymus, yet they have not acquired cortisone resistance, a trait normally attributed to this mature thymic subset. It appears that the GVH dysplastic thymus can support the differentiation of L3T4+Lyt-2- cells--however, such a thymus is unable to confer cortisone resistance upon this population. Consequently, these cells appear to be eliminated when exposed to corticosteroids in peripheral lymphoid tissue.

Acquired Immunodeficiency Syndrome↗
PubMed1991

The effect of the graft-versus-host reaction on B lymphocyte production in bone marrow of mice. Depressed genesis of early progenitors prior to mu heavy chain expression.

The effects of systemic graft-versus-host (GVH) reactions on the early precursor cell populations involved in primary B lymphocyte genesis have been examined in the bone marrow of (C57BL/6xA)F1 mice injected with lymphoid cells from A strain mice. Double immunofluorescence labeling techniques for the intranuclear enzyme, terminal deoxynucleotidyl transferase (TdT), the B220 cell surface glycoprotein detected by monoclonal antibody, 14.8, and surface or cytoplasmic mu chains of IgM (s mu, c mu) were used to quantitate 3 putative early B lineage progenitors preceding mu chain expression (TdT+14.8-mu-, TdT+14.8+mu- and TdT-14.8+mu-), pre-B cells (c mu+, s mu-) and B lymphocytes (s mu+). After initiating GVH reactions, the early B precursor cells, pre-B cells, and B lymphocytes in the bone marrow all fell rapidly in numbers, being almost completely absent from 10-15 days to the end of the 30-day assay period. The decline of some of the early progenitors started at a later time and was less complete than that of the more differentiated B lineage cells. In the spleen, B lymphocytes declined rapidly in numbers after 8 days to less than 5% of normal values from 12 days onward. The results demonstrate that systemic GVH reactions in mice almost completely eliminate the B cell lineage, including early precursor cells apparently undergoing mu chain rearrangement in the bone marrow. The pattern of depletion suggests that a range of B lineage progenitor cells may be directly susceptible to GVH reactions. The findings contribute to a model for the pathogenesis of the humoral immunodeficiency of systemic GVH disease.

Animals↗