Recruitment of null cells during graft versus host reactions in the chicken

Untreated SC (B2/B2) chicken spleen or thymus cells (2 × 10⁷) caused significantly increased [³H]thymidine incorporation in spleens of heavily irradiated FP (B15/B21) recipient chicks on Day 4 after iv injection. Mitomycin-treated SC spleen cells or spleen cells treated with rabbit anti-T-cell serum and complement failed to raise the [³H]thymidine incorporation over that in uninjected, bursa cell-injected or FP spleen cell-injected controls. However, the combination of mitomycin-treated spleen or thymus cells and anti-T-treated spleen cells caused an increased [³H]thymidine uptake, suggesting the recruitment of non-T cells into proliferation by alloreactive mitomycin-treated T cells. Bursa cells did not proliferate during GVH reactions even though they could be shown to undergo proliferation in vivo upon mitogen (lipopolysaccharide and dextran sulfate) stimulation. In contrast, anti-T-treated spleen cells from agammaglobulinemic chickens were recruited into proliferation, suggesting that the recruited cell was not only not a T cell, but also no pre-B or B cell and most likely represented a cell of the monocyte-macrophage series.     

In vitro sensitization to transplantation antigens. VII. Enhanced graft-vs-host activity of in vitro allosensitized lymphoid cells

We have previously demonstrated that C57BL/6J lymphoid cells sensitized in vitro to C3H/He transplantation antigens, present on macrophage monolayers, can transfer an accelerated C3H allograft response to recipient C57 mice. The present report indicates that C57 lymphoid cells sensitized to C3H alloantigens, present on macrophage monolayers, can also mediate a graft-versus-host (GVH) reaction in (C3H × C57) F₁ newborn mice. This GVH reaction is of greater magnitude than that produced by noncultured C57 cells. The magnitude of the augmented GVH reaction produced by cultured C57 cells is dependent on the source of lymphoid cells: lymph node, spleen, and bone marrow cells are consistently more active than cultured thymus cells—the reduced capability of cultured thymus cells to mediate the GVH reaction parallels their reduced ability to transfer allograft immunity. To test whether monolayers, other than macrophages, can sensitize lymphoid cells in vitro we incubated C57 lymphoid cells on C3H-derived L cells. Lymph node cells incubated with L cells demonstrate an increased GVH reaction in newborn mice. The in vitro sensitization of spleen and bone marrow cells on L cells is less consistent. Thymus cannot be sensitized by L cells. Monolayers of L cells are therefore not as efficient a sensitizing source as macrophages.     

Effect of allogeneic cell interaction and graft-versus-host reaction on the antibody response to Escherichia coli 0127 antigen.

The influence of allogeneic cell interaction and GVH reaction on the immune response to Escherichia coli antigen was investigated. Addition of CBA/J spleen cells to cultures of nu/nu spleen cells stimulated a significant increase in the nude PFC response to SRBC but had no significant effect on the immune response to E. coli antigen. Similarly, the induction of a GVH reaction in F₁ mice by the injection of parental spleen cells also had no significant effect on the immune response to the bacterial antigen. These results suggest that the immune response to E. coli is not affected by products of thymus-derived cells.     

Apparent T cell function of bone marrow cells from mice experiencing a graft-versus-host reaction.

The graft-versus-host (GVH) reaction, induced in adult F₁ mice by the injection of parental strain lymphoid cells (GVH mice), suppressed the in vitro plaque-forming cell (PFC) response to sheep erythrocytes (SRBC) of spleen cells obtained from the GVH mice (GVH-SC). In vitro restoration of the PFC response of GVH-SC was carried out employing a modified Marbrook culture chamber consisting of an inner culture compartment (IC) separated from an outer culture compartment (OC) by a cell-impermeable membrane. Thymus cells (TC) and lymph node cells (LNC) but not bone marrow cells (BMC) from normal mice placed in the IC restored the PFC response of GVH-SC cultured with SRBC in the OC. The restoring ability of TC and LNC was markedly reduced following treatment with anti-theta serum plus complement. BMC taken from GVH mice 3 or more days post-GVH induction (GVHBMC) and placed in the IC restored the PFC response of GVH-SC as well as TC and LNC. Treatment of GVH-BMC with anti-theta serum plus complement did not affect their restoring ability; furthermore, the number of theta-bearing cells in the bone marrow did not increase as a consequence of the GVH reaction. Two possible explanations are proposed for the T-like function of GVH-BMC.     

Nonspecific suppressor elements in murine allogeneic radiation chimeras.

Spleen cells from long-term mouse allogeneic radiation chimeras were tested for their ability to modulate the graft-versus-host (GVH) or plaque-forming cell (PFC) response of normal lymphocytes transplanted in lethally X-irradiated recipients. In vivo GVH proliferation of normal lymphocytes (syngeneic to donor cells of the chimera) against antigens of host-type in which the chimeric state had been established was reduced by chimera cells. Inhibition varied, some chimeras suppressing GVH more than others and a few not suppressing at all. The suppressive effect was abrogated if the chimera cells were treated with anti-θ; treatment with anti-IgM did not eliminate this activity. When mixtures of normal donor lymphocytes and chimera cells were given to irradiated recipients genetically different from host or donor, reduction of donor cell GVH also occurred. Further, chimera cells reduced the GVH activity of normal host cells in irradiated recipients differing from the host at one H-2 locus and from the donor at minor histocompatibility loci. The modulating effect of spleen cells from chimeras on the PFC response by normal lymphocytes also varied. Six chimeras induced a 25 to 90% suppression, two enhanced the response, and one showed no effect. Where suppression occurred, treatment of chimera cells with anti-θ most often, but not always, restored PFC production. Our results show that the suppressive action of splenic lymphoid cells by chimeras is highly nonspecific and variable in expression. We suggest that tolerance in chimeras may be mediated by nonspecific suppressor elements leading to unresponsiveness to a variety of antigens including SRBC.     

Graft-versus-host induced immunosuppression: depressed T cell helper function in vitro.

The cause of graft-versus-host (GVH) induced suppression of the plaque forming cell (PFC) response to sheep erythrocytes (SRBC) was investigated by in vitro restoration experiments employing a double compartment culture vessel. The two culture compartments were separated by a cell impermeable membrane. Restoring cells were placed in one chamber and responding GVH spleen cells plus SRBC were placed in the other chamber. It was demonstrated that thymus, lymph node, and spleen cells restored the PFC response whereas bone marrow cells did not. Treatment of the restoring cells with anti-theta serum plus complement abrogated restoration. Supernatants obtained from antigen free cell cultures restored nearly as well as whole cell suspensions. The degree of restoration was not increased by allogeneic or xenogeneic antigenic stimulation of the restoring cells. Thymus and lymphoid cells obtained from animals experiencing a GVH reaction restored as well as normal cells, however spleen cells were unable to restore by day 5 post-GVH induction. The results suggest that GVH induced immunosuppression of the PFC response is due, at least in part, to a depressed T cell factor production by splenic T cells.     

Prostaglandin synthesis by lymphoid tissue of mice experiencing a graft-versus-host reaction: relationship to immunosuppression

Studies were carried out on the induction of PGE synthesis during the GVH reaction and its role in GVH-induced immunosuppression. The results demonstrated that spleen, lymph node cells and, to a much lesser degree, thymus cells obtained from adult C57BL/6 × AF₁ mice treated with 50–75 × 10⁶ C57BL/6 lymphoid cells were stimulated to produce PGE during the course of the GVH reaction. The spleen and lymph node PGE production peaked at Day 9 post-GVH induction (30- and 15-fold higher than normal, respectively). Thereafter, it declined to near normal levels by Days 25–30 post-GVH induction. Passage of GVH spleen cells through a rayon column removed macrophages but not mitogen-responsive T and B cells and also removed nearly all of the PGE-producing cells, except during the later course of the GVH reaction. Removal of PGE-producing cells from GVH-immunosuppressed spleen cells significantly reconstituted the mitogen response to PHA and LPS. Treatment of mice experiencing a GVH reaction with indomethacin delayed the onset of suppression of the plaque-forming cell response to sheep erythrocytes. These results suggest that early GVH-induced immunosuppression which may represent an amplified normal regulatory mechanism is mediated by increased macrophage production of PGE which suppresses both B- and T-cell functions, whereas at later stages other immunosuppressive mechanisms become operational.     

Cellular immunity in the mouse. IV. Altered thymic-dependent lymphocyte reactivity in the chronic graft vs host reaction and leukemia virus activation.

The lymphocytes obtained from several F₁ strains undergoing chronic GVH reactions were studied for in vitro alterations of thymic-dependent lymphoid function. Spontaneous blastogenesis was increased. The in vitro response to nonspecific mitogenic stimuli (PHA and CON-A) and specific antigenic challenge (SRBC and allogeneic cells) was initially increased and subsequently impaired. The degree of alteration was related to the severity of the observed disease and dependent upon the F₁-parental combination employed. Thymic-dependent lymphocytes obtained from animals with GVH disease possessed the ability to suppress actively the response of normal mouse cells in vitro to various T-cell mitogenic stimuli and this suppressive activity was present in the supernatant culture fluid from such cells. The mechanism of this altered in vitro T-cell reactivity is not yet completely understood, but may in part be related to the immunologic activation of murine leukemia virus from mouse cells undergoing allogeneic stimulation.     

Fate of H2-activated T lymphocytes in syngeneic hosts. III. Differentiation into long-lived recirculating memory cells.

Memory to H2 determinants was studied with an adoptive transfer system using a population of H2-activated blast T cells (T.TDL) obtained from thoracic duct lymph of irradiated F₁ hybrid mice injected with parental strain T cells. CBA T.TDL activated either to DBA/2 or C57BL determinants were transferred to syngeneic “B” mice. Thoracic duct lymphocytes (TDL) were obtained from the recipients 4–6 weeks later and tested for their capacity to produce (a) a graft-versus-host (GVH) reaction, (b) a mixed lymphocyte reaction (MLR) (measured by an in vivo technique) and (c) allograft rejection (suppression of the growth of allogeneic tumour cells in vivo). Control experiments involved testing the function of TDL obtained from “B” mice preinjected with TDL or no cells.TDL from “B” mice injected with TDL (passaged TDL) gave strong MLR and GVH reactions to both DBA/2 and C57BL determinants. Passaged T.TDL activated to C57BL antigens gave intermediate MLR and GVH reactions to the specific (C57BL) determinants but only very low responses to third-party (DBA/2) determinants; reciprocal results were obtained with passaged T.TDL activated to DBA/2 determinants. TDL from “B” mice given no cells failed to respond to either set of determinants.Since the responses by the passaged T.TDL did not exceed those by passaged TDL there was no evidence that adoptive transfer of T.TDL had conferred to the recipients a state of memory to either MLR or GVH determinants. Adoptive transfer did, however, lead to qualitative changes in the properties of T.TDL since, before transfer, they were unable to evoke GVH reactions or produce an MLR of normal kinetics.Passaged T.TDL were far superior to passaged TDL at suppressing the growth of allogeneic tumour cells. The protection was specific since protection against DBA/2 tumour cells was, cell for cell, 5–10 fold more effective with passaged T.TDL activated to DBA/2 determinants than with cells activated to C57BL determinants. No protection was observed with cells treated with anti-θ serum. The protective cells appeared to be precursors of effector cells rather than effector cells per se since they failed to lyse the tumour cells in vitro. These data suggest therefore that the descendants of T.TDL which survived after transfer to “B” mice were highly enriched in long-lived recirculating T lymphocytes reactive to determinants expressed by specific tumour allografts.     

Cellular immunity and blocking serum activity in chimeric mice

Mice (9 CBA × T6, 6 T6, and 7 CBA) were irradiated and repopulated with foreign (BALB/c) bone marrow. Lymph node cells from 16 of 18 repopulated mice not showing signs of graft versus host disease (GVH), were cytotoxic to host type fibroblasts but not to BALB/c fibroblasts, and sera from the same mice could block lymphocyte mediated cytotoxicity. No blocking was seen with sera from three mice which had signs of GVH. LNC from the latter three mice were cytotoxic to recipient fibroblasts.It is suggested that the blocking effect detected in vitro may protect against GVH in vivo, but the relative importance of the blocking phenomenon as compared to other mechanisms is not yet settled.     

Antigen-presenting B cells: efficient uptake and presentation by activated B cells for induction of cytotoxic T lymphocytes against vesicular stomatitis virus

We have evaluated the efficacy of mitogen (LPS/DxSO4)-activated B cells (B lymphoblasts) to function as antigen-presenting cells (APC) for vesicular stomatitis virus (VSV). Our studies revealed that B lymphoblasts induced potent cytotoxic thymus (T)-derived lymphocyte (CTL) activity in VSV-immune splenic T cells depleted of adherent accessory cells. Dose-response curves indicated that B lymphoblasts were approximately 15-20 times more efficient APC than spleen cells for CTL induction against VSV. There was little evidence of reprocessing of viral antigens by the responder population because only CTL activity restricted to the parental haplotype of the B lymphoblast was generated following stimulation of VSV-immune F1 T cells. B lymphoblasts activated VSV-specific memory CTL which expressed the Lyt-1-23+, AsGM1+ phenotype without activating natural killer and/or lymphokine-activated killer cells. The ability of B lymphoblasts to function as efficient APC was not related to enhanced viral replication in these cells because potent VSV-specific proliferative and class I-restricted CTL responses were induced by B lymphoblasts infected with VSV rendered noninfectious by exposure to ultraviolet (uv) light. This indicates that activated B cells can efficiently process and present input virion protein. Purified splenic B cells that were not activated by mitogen stimulation did not function as APC for VSV even at high multiplicities of infection. The failure of B cells to function as APC for VSV was related to inefficient uptake of VSV and their inability to provide accessory cell signals required for T-cell proliferation; both these functions developed following mitogen stimulation. These data suggest that activated B cells may function as a potent APC population for virus independent of the specificity of their immunoglobulin antigen receptor.     

Targeting the apoptotic pathway with BCL-2 inhibitors sensitizes primary chronic lymphocytic leukemia cells to vesicular stomatitis virus-induced oncolysis

Chronic lymphocytic leukemia (CLL) is characterized by clonal accumulation of CD5⁺ CD19⁺ B lymphocytes that are arrested in the G₀/G₁ phase of the cell cycle and fail to undergo apoptosis because of overexpression of the antiapoptotic B-cell CLL/lymphoma 2 (BCL-2) protein. Oncolytic viruses, such as vesicular stomatitis virus (VSV), have emerged as potential anticancer agents that selectively target and kill malignant cells via the intrinsic mitochondrial pathway. Although primary CLL cells are largely resistant to VSV oncolysis, we postulated that targeting the apoptotic pathway via inhibition of BCL-2 may sensitize CLL cells to VSV oncolysis. In the present study, we examined the capacity of EM20-25—a small-molecule antagonist of the BCL-2 protein—to overcome CLL resistance to VSV oncolysis. We demonstrate a synergistic effect of the two agents in primary ex vivo CLL cells (combination index of 0.5; P < 0.0001). In a direct comparison of peripheral blood mononuclear cells from healthy volunteers with primary CLL, the two agents combined showed a therapeutic index of 19-fold; furthermore, the combination of VSV and EM20-25 increased apoptotic cell death in Karpas-422 and Granta-519 B-lymphoma cell lines (P < 0.005) via the intrinsic mitochondrial pathway. Mechanistically, EM20-25 blocked the ability of the BCL-2 protein to dimerize with proapoptotic BAX protein, thus sensitizing CLL to VSV oncolytic stress. Together, these data indicate that the use of BCL-2 inhibitors may improve VSV oncolysis in treatment-resistant hematological malignancies, such as CLL, with characterized defects in the apoptotic response.     

Genetics of graft-versus-host reactions (GVHR)

Injection of 20×10⁶ donor lymph node cells (LNCs) into newborn allogeneic recipients incompatible with donors at theIC subregion of the mouseH-2 complex evoked both GVH splenomegaly and GVH mortality. The strength or severity of the allogeneic reactions induced varied as a function of the interallelic strain combination and was influenced particularly by properties of the recipientIC determinants. Thus,IC ^s determinants on recipient cells led to strong GVHR, whileIC ^d determinants induced a moderate GVHR, even when donors carrying differentIC alleles were used. However, responder donor genes also affected the degree of GVHR in some combinations. The effect on donor GVH potential of pre-exposing B10 donors to antirecipient antiserum (B10 anti-B10.A) was also studied. Spleen cells from B10 donors pre-exposed to alloantiserum for two to seven days exhibited a markedly reduced ability to cause GVH splenomegaly and GVH disease in newborn B10. A or (B10. A × B10) F₁ recipients. Inhibition of donor lymphocyte GVH potential waned eight to 14 days after antiserum pretreatment. Inhibition was shown to be specific for variousH-2 determinants and to be caused by antirecipient alloantibodies. Pre-exposure of donors to alloantiserum reduced the GVH potential of spleen cells but did not affect LNC reactivity.Ia antibodies and, to a lesser extent, anti-H-2D serum were shown to be able to inhibit GVHR. The results suggest that the observed reduction in donor GVH reactivity is caused by antibody-mediated central feedback inhibition. Anti-H-2 alloantibodies evidently play an important role in the network regulating allogeneic responses.     

Stimulation of humoral immune responses to a thymic-independent antigen in mice immunosuppressed by a graft-versus-host reaction.

The immunosuppressive effect of the graft-versus-host (GVH) reaction was studied in CBA × A F₁ (CAF₁) mice which had been rendered immunologically unresponsive by the injection of parental A-strain lymphoid cells (GVH mice). When challenged with a single injection of either sheep red blood cells or Escherichia coli lipopolysaccharide (LPS), GVH mice failed to produce a significant number of plaque-forming cells (PFC) or a significant level of antibody against either the thymic-dependent or the thymic-independent antigen. Multiple challenges with SRBC also failed to stimulate a significant humoral immune response to the thymic-dependent antigen. Multiple challenges with LPS, however, resulted in the production of a significant number of LPS-specific PFC and a high titer of anti-LPS hemagglutinating antibodies. These results suggest that GVH-induced suppression of humoral immune responses is directed partly at B-cell activity and partly at the activity of helper T cells.     

Detection of nonspecific cytotoxicity in graft-versus-host reaction as a function of target cell type

The cytotoxic activity of spleen cells from mice undergoing graft-versus-host (GVH) reaction on ⁵¹Cr-labeled target cells was studied under in vitro conditions. Among normal tissues used as target cells, skin fibroblasts proved to be most sensitive to the nonspecific cytotoxic effects of spleen cells from mice undergoing GVH reaction, whereas kidney cells or macrophages were insensitive to these nonspecific cytotoxic effects. Of the two murine neoplastic target cells used, Sarcoma 1 cells were susceptible to these nonspecific cytotoxic effects whereas mastocyoma cells were resistant. However, the target cells which were insensitive to the nonspecific cytolytic effects, were lysed specifically by the spleen cells from animals specifically sensitized. Therefore, both specific and nonspecific cytotoxic effects of spleen cells from mice undergoing GVH reaction could be detected with appropriate targets. These results provide a basis for reconciliation of several apparently contradictory results, reported in the literature, concerning the specificity of the cytotoxic effects of specifically sensitized lymphocytes.     

Regulation of the in vitro anamnestic antibody response by cyclic AMP. II. Antigen-dependent enhancement by exogenous prostaglandins of the E series.

The spleen cells from CFW/D mice injected with dimethylbenzanthracene-induced leukemia virus exhibited a progressive decline in the in vitro response to heterologous erythrocyte antigens in parallel with tumor growth. Cell transfer experiments revealed that this immunodepressed state may involve a B-cell defect rather than extrinsic factors in the cellular environment since: (i) nonresponsiveness could be transferred to irradiated non-tumor-bearing mice with spleen cells, and (ii) T cells from tumorbearing mice cooperated with normal bone marrow cells, but bone marrow from tumorbearing mice did not cooperate with normal T cells. In addition, T cells from the thymic tumor could cooperate with normal bone marrow cells upon transfer to irradiated recipients. TL 485-2 cells, a T-cell line derived from the tumor, could be specifically activated with SRBC thereby indicating that the virus transformed T cells were immunocompetent. Suppressor cells, which appeared in the spleen concomitant with immunodepression and tumor development, may directly raise B-cell thresholds for T-dependent triggering signals since the antibody response of spleen cells from tumor-bearing mice could be restored by adding agents such as LPS, 2 mercaptoethanol, or T cells exogenously preactivated in normal animals. The suppressor cell could be enriched by adherence to plastic and was removed by treatment with carbonyl iron. In addition, it was unlikely that the suppressor cell was a virus-infected cell since transformed, virus-infected cells from the tumor or TL 485-2 cells were not suppressive when added to spleen cells in vitro but rather resulted in a marked, polyclonal enhancement of the PFC response. The interaction of TL 485-2 cells and normal spleen cells resulted in the release of a stimulatory factor which increased DNA synthesis in resting cells as well as increasing PFC. The role of these enhancing factors and suppressor cells in controlling tumor growth remains to be elucidated.     

Graft-vs-host reactions (GVHR) across minor murine histocompatibility barriers. I. Impairment of mitogen responses and suppressor phenomena

In our laboratory, we have developed a murine model to examine GVHD across minor histocompatibility antigens. In our model, GVHD is induced by injecting B10.D2 spleen cells into irradiated BALB/c recipients. Seven to 10 days after irradiation and injection of cells, there are significant changes in cell function in the recipient spleens. In the B10.D2----BALB/c (600 rad) model, recipient spleen cells are profoundly unresponsive to Con A and LPS stimulation but show increased B cell activity measured by Staphylococcus aureus protein A plaque-forming activity. Spleen cells from such GVH mice profoundly suppress the mitogenic responses of normal BALB/c or B10.D2 spleen cells to Con A and LPS. The degree of impairment of the mitogenic response and the ability to suppress normal cells is proportional to the dose of cells used to induce GVH reactions. Both the inability to respond to mitogens and the capacity to suppress are also related to the dose of irradiation given to the recipients. In addition, immunosuppression across minor histocompatibility antigens shows an unevenhandedness. If we inject parental B10.D2 or BALB/c cells into F1 recipients (P----F1), there is greater inhibition of mitogenic responses when B10.D2 parental cells are given than when BALB/c cells are given to the irradiated F1 recipients. These experiments show that significant immunosuppression occurs during GVH reactions across minor histocompatibility barriers. The degree of suppression varies according to the dose of cells used to induce GVH, the dose of irradiation to the recipient and the "strength" of the GVH recognition system. Such experiments provide models for GVH disease seen in humans who receive treatment for leukemia or other diseases that involves recipient irradiation and infusion of HLA-identical bone marrow.     

Role of cytotoxic T lymphocytes in the prevention of lupus-like disease occurring in a murine model of graft-vs-host disease

The inoculation of B6D2F1 mice with T lymphocytes from the C57BL/6 parental strain induces an "immunosuppressive" graft-vs-host reaction (B6 GVH), whereas inoculation of T cells from the other, DBA/2 parental strain induces an "immunostimulatory" GVH reaction and a lupus-like disease (DBA GVH). The present study compares cytotoxic T lymphocyte (CTL) function in the spleens of these GVH mice as well as differences in the donor inoculum that could account for these different types of GVH. We observed that the B6 GVH induces an immunodeficiency that encompasses CTL precursors (and possibly T helper cells) and results in suppressor cells that abrogate responses to both trinitrophenyl (TNP)-modified self and third party alloantigens. In contrast, the DBA GVH induces only a T helper cell immunodeficiency and results in suppressor cells selective for class II restricted L3T4+ T helper cells. Chimeric T cells were detected in both types of GVH. In the B6 GVH both L3T4+ and Lyt-2+ donor cells were observed, although Lyt-2+ cells predominated. In the DBA GVH, donor T cells were almost exclusively of the L3T4+ phenotype. The lack of appreciable donor Lyt-2+ cells in the DBA GVH can be explained by a defect in the DBA donor inoculum manifested by a naturally occurring two-fold reduction in Lyt-2+ cell numbers as well as a nine-fold reduction in CTL precursors with anti-F1 specificity. T cells in the DBA inoculum, therefore, are predominantly L3T4+. A similar defect induced in B6 donor cells by anti-Lyt2 antibody and complement not only converted the suppressive GVH to a stimulatory GVH, as measured by anti-DNA antibodies, but also resulted in a T cell immune deficiency characteristic of the DBA GVH, i.e., a selective loss of the TNP-self CTL response. Thus the presence or absence of adequate numbers of functioning Lyt-2+ cells in the donor inoculum is correlated with the development of either a suppressive or stimulatory GVH, respectively. That donor Lyt-2+ cells mediate a suppressive GVH through cytolytic mechanisms is evidenced by greater than 70% reduction in B6 GVH spleen cell numbers and readily demonstrable anti-F1 CTL activity by these spleen cells despite an inability to generate anti-allogeneic or anti-TNP self CTL activity even in the presence of added T helper factors.(ABSTRACT TRUNCATED AT 400 WORDS)     

Neonatal infection with mouse thymic virus. Differential effects on T cells mediating the graft-versus-host reaction.

Neonatal infection with mouse thymic virus (TA), a murine herpes virus, produced extensive but temporary necrosis of the thymus which was maximal at 10 to 14 days of age. Studies of precursor and amplifier cells mediating graft-vs-host (GVH) reactivity of thymocytes, spleen cells (SC), and lymph node cells (LNC) of normal and TA-infected mice were made at 4 and 8 weeks of age. Infection with TA resulting in a profound reduction (70 to 80%) in the direct GVH reactivity of thymocytes at both ages; by comparison, the capacity of thymocytes to produce synergy when combined with normal LNC was normal at 8 weeks. Direct GVH reactivity of SC was depressed 90% 4 weeks after infection with TA but returned to near normal at 8 weeks. Direct GVH reactivity of LNC from TA-infected mice was normal at 4 and 8 weeks of age, but amplifier T cell activity in LNC was markedly depressed at 8 wekks. These results demonstrate that TA has highly selective effects upon subpopulations of T cells in thymus and lymph node.     

Effect of vesicular stomatitis virus (VSV) infection on the development and regulation of T cell-mediated immune responses

Infection of mice with vesicular stomatitis virus (VSV) at the time of immunization failed to enhance T cell-mediated immune response to azobenzenearsonate-(ABA) conjugated spleen cells as measured by delayed-type hypersensitivity and by in vitro proliferation and in vitro generation of ABA-specific cytotoxic T cells. However, mice infected with VSV are incapable of responding to signals from suppressor T cells or their soluble factors. Further analysis revealed that VSV infection does not interfere with the induction of Ts-1 or Ts-2 cells. Because infection of Ts-1 or Ts-2 donors had no effect on the subsequent response seen in the recipients of antigen and suppressor T cells, the most likely candidate for the target of VSV infection is therefore the Ts-3 cell or another T cell interacting with Ts-3. This is supported by our observation that it is possible to bypass the VSV effect by providing the recipients of VSV with normal Lyt-2+-bearing T cells.