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Biomedical subjects

R Korngold

Publications and source records attributed to R Korngold.

At least 91 records · Page 5Linked to original sources
PubMed1985

Surface markers of T cells causing lethal graft-vs-host disease to class I vs class II H-2 differences.

Information was sought on the phenotype of lymphoid cells causing lethal graft-vs-host disease (GVHD) in irradiated mice expressing whole or partial H-2 differences. In all strain combinations tested, pretreating donor lymph node (LN) cells with anti-Thy-1 monoclonal antibodies (MAb) plus complement (C) abolished mortality. With GVHD directed to class I H-2 differences, pretreating LN cells with anti-Lyt-2 MAb prevented mortality, whereas MAb specific for Ly-1 or L3T4 cell surface determinants caused severe mortality. These data imply that lethal GVHD directed to class I H-2 differences is mediated by L3T4-, Lyt-2+ cells; this subset of T cells was shown previously to control GVHD directed to multiple minor histocompatibility antigens, i.e., antigens seen in the context of self-class I molecules. With whole H-2 differences, GVHD appeared to be controlled largely but not exclusively by L3T4+, Lyt-2-T cells. This T cell subset was also the predominant cause of GVHD directed to class II differences. With class II incompatibilities, depleting donor cells of L3T4+ T cells, either by pretreatment with anti-L3T4 MAb + C or by fluorescence activated cell sorter selection, greatly reduced but did not completely abolish GVHD. These data might imply that L3T4-, Lyt-2+ cells have some capacity to elicit anti-class II GVHD. A more likely possibility, however, is that the residual GVHD to class II differences observed with Lyt-2+-enriched cells reflected minor contamination with L3T4+ cells.

Animals↗
PubMed1984

The localized primary cytotoxic T-cell response to cells expressing minor histocompatibility differences.

Cytotoxic T lymphocytes (CTL) are able to eliminate P815 (DBA/2) mastocytoma cells growing in cerebrospinal fluid of BALB/c H-2-compatible but minor histocompatibility (H) antigen-different mice and in H-2-incompatible C3H/He mice. We examined the magnitude of the primary CTL response to multiple, minor H antigens and to determinants of the major histocompatibility complex (MHC) by using a direct cytolytic assay and limiting-dilution analysis to estimate CTL frequency. By these criteria, no obvious differences emerged, and the responses appeared comparable at the site of inflammatory process, despite differences in the number of clonal progenitors. Experiments with radiation chimeras showed evidence of a strong cytotoxic T-cell response against P815 cells in [(ddd X bbb)F1----ddd] and (F1----bbd), but not in (F1----bbb) radiation chimeras. Therefore, this cytotoxic T-cell response against minor H antigens obeys the postulated rules for thymic restriction of precursors. Compatibility at the H-2 D-end of the MHC is apparently sufficient to ensure a strong response.

Animals↗
PubMed1984

Spontaneous interstitial nephritis in kdkd mice. I. An experimental model of autoimmune renal disease.

Mice of the kdkd strain predictably develop a spontaneous tubulointerstitial nephritis after 8 wk of life. In this report we have examined several aspects of the nephritogenic immune response that seemed potentially relevant to the expression of this progressively destructive renal lesion. Of particular interest is that by direct immunofluorescence we were unable to demonstrate the presence of antibodies to determinants in the tubulointerstitium. Serum and kidney eluates from nephritic mice, furthermore, did not stain any renal structures in normal kidney. We did observe, however, that disease could be transferred through kdkd----CBA/Ca bone marrow chimeras, and prevented, in the reverse direction, by CBA/Ca----kdkd chimeras. The development of the interstitial lesion was markedly inhibited by thymectomy with T cell depletion, but disease could not be adoptively transferred with cells or serum from nephritic mice. The interstitial lesions also did not appear in (kdkd X CBA/Ca)F1 hybrids, and the development of disease in kdkd mice could be inhibited by treatment with adoptively transferred T cells from CBA/Ca mice. With these new findings we now hypothesize that susceptibility to the expression of interstitial nephritis in kdkd mice involves the cellular limb of the immune system, and may be related, in part, to alterations in regulatory T cell function.

Animals↗
PubMed1983

Specific and nonspecific T-cell recruitment in viral meningitis: possible implications for autoimmunity.

Specific and nonspecific T-cell invasion into cerebrospinal fluid has been investigated in the nonfatal viral meningoencephalitis induced by intracerebral inoculation of mice with vaccinia virus. At the peak of the inflammatory process on Day 7 approximately 5 to 10% of the Lyt 2+ T cells present are apparently specific for vaccinia virus. Concurrently, in mice primed previously with influenza virus, 0.5 to 1.0% of the appropriate T-cell set located in cerebrospinal fluid is reactive to influenza-infected target cells. This vaccinia virus-induced inflammatory exudate may thus contain as many as 500 influenza-immune memory T cells. These findings are discussed from the aspect that such nonspecific T-cell invasion into the central nervous system during aseptic viral meningitis could result in exposure of potentially brain-reactive T cells to central nervous system components.

Animals↗
PubMed1983

Hierarchies of T cell responsiveness are reflected in the distribution of effector T cells in viral meningitis.

The vaccinia-virus-immune cytotoxic T lymphocyte (CTL) response, associated with H-2Kk in B10,A(2R) [KkDb] mice, is much more potent than that occurring in the context of H-2Db. This differential reactivity is true for T-cells recovered either from cerebrospinal fluid (CSF) of mice injected intracerebrally (i.c.) with a low dose of virus or from spleen populations primed by intravenous (i.v.) inoculation of a large amount of virus. Further stimulation of CSF inflammatory cells in vitro for 7 days under limiting dilution conditions indicated that the hierarchy of cytotoxic T-cell activity was a function of the relative frequencies of H-2Kk- and H-2Db-restricted lymphocytes. We therefore conclude that the immune response gene effect described previously for cells found in lymphoid tissue is also expressed in a virus-induced inflammatory exudate in the central nervous system.

Animals↗
PubMed1983

Characteristics of poxvirus-induced meningitis: virus-specific and non-specific cytotoxic effectors in the inflammatory exudate.

Mice injected intracerebrally with a sublethal dose of vaccinia virus develop severe meningitis. The number of inflammatory cells in cerebrospinal fluid (CSF) increases approximately threefold each day for 3 to 7 days after intracerebral challenge, subsequent to which samples can no longer be obtained because the cisterna magna is obliterated owing to brain swelling. Examination of this inflammatory exudate during the later stages of this pathological process shows evidence of both cytotoxic T lymphocyte (CTL) function and the presence of Lyt1+ and Lyt2+ cells on days 6 and 7. In addition, potent non-T-cell (Lyt2-) cytotoxic activity is found in CSF taken from younger (12 weeks) mice as early as after day 3 and is still present on day 6. The level of non-T-cell-mediated cytotoxicity in CSF on day 5 or 6 (but not day 3) is considerably decreased in animals that were also given a large dose of virus intravenously to maximize T-cell stimulation in lymphoid tissue, and the extent of CTL activity is concomitantly increased. The diminution of non-specific cytotoxic function does not seem to reflect simple dilution in the presence of excess virus-immune T cells.

Animals↗
PubMed1983

Lethal GVHD across minor histocompatibility barriers: nature of the effector cells and role of the H-2 complex.

Transfer of T-cells to heavily irradiated, H-2-compatible mice frequently leads to a high incidence of lethal graft-versus-host disease (GVHD). Lymphoid cells depleted of Thy1+ cells fail to cause GVHD. Studies with a variety of different, H-2-compatible, strain-combinations suggest that minor, histocompatibility antigens (minor HA) are the main targets for eliciting lethal GVHD. Experiments in which T-cells are negatively selected to minor HA by acute blood-to-lymph recirculation through irradiated hosts have indicated that the T-cells eliciting GVHD to minor HA, are H-2-restricted. In H-2-compatible hosts, the donor T-cells recognize the minor HA of the host and become temporarily trapped in the lymphoid tissues for 1-2 days; during this stage of negative selection, the donor T-cells entering the lymph are specifically devoid of cells able to elicit GVHD against the host, minor HA on further transfer. When the selection host is H-2-different with respect to the donor T-cells, by contrast, the T-cells ignore the host, minor HA and negative selection fails to occur. The T-cells recirculate normally and are unimpaired in their capacity to elicit GVHD on further transfer. By the use of various H-2-recombinant mice as selection hosts it has been shown that, as for T-cells exerting cell-mediated lympholysis (CML) to minor HA in vitro, the T-cells which elicit lethal GVHD to minor HA comprise two distinct subsets of H-2-restricted cells. One subset recognizes minor HA in the context of H-2K (or K end) molecules whereas the other is specific for minor HA-plus-H-2D. Curiously, in marked contrast to the findings on CML responses in vitro, no evidence has been found that H-2I-restricted T-cells contribute to GVHD, either as effector cells or as helper cells. Purified populations of Lyt 1-2+ T-cells have potent GVHD activity, whereas Lyt 1+2- cells fail to cause GVHD. Studies with various types of bone-marrow chimeras suggest that in the induction phase, T-cells recognize minor HA only on lymphohematopoietic cells. In the effector phase, by contrast, non-marrow-derived cells appear to be the main targets of attack. Although the pathogenesis of GVHD is poorly understood, the lethal form of the disease probably reflects the penetration of mucosal surfaces by pathogenic organisms, perhaps as the result of direct destruction of epithelial cells by minor HA-specific cytotoxic lymphocytes. Direct support for this notion has yet to be obtained.

Animals↗
PubMed1983

Effect of interferon on thoracic duct lymphocyte output: induction with either poly I:poly C or vaccinia virus.

Systemic inoculation of the interferon (IFN) inducer polyinosinic-polycytidylic polyribonucleotide (poly I:poly C) into CBA/J mice produces a significant decrease in the number of thoracic duct lymphocytes (TDL) collected 6 to 22 hr after injection. The number of TDL is restored to normal levels by 48 to 64 hr. Residual TDL collected during the inhibition period of poly I:poly C treatment showed a phenotypic profile similar to phosphate-buffered saline- (PBS) treated control groups when examined for Lyt-1.1, Lyt-2, Thy-1.2 and Iak surface markers. Interferon is implicated as the mediator of this phenomenon since: 1) Inoculation of exogenous IFN can induce a similar suppression in the number of recoverable TDL. 2) Pretreatment of mice with sheep anti-murine IFN serum can block this effect of poly I:poly C. Similar experiments with vaccinia virus demonstrate that although live virus can partially suppress the TDL output, almost complete suppression is achieved with ultraviolet (UV)-inactivated virus. Vaccinia virus-induced suppression of the number of TDL also appears to be caused by IFN since: 1) UV-inactivated virus induces significantly higher serum levels of IFN in comparison to live virus. 2) The suppression of TDL output by either live or UV-inactivated vaccinia virus can be blocked by pretreatment with anti-murine IFN. These findings suggest that the immunosuppression often associated with viral infections may be at least partially due to a decrease in lymphocyte recirculation mediated by the IFN initially released in response to the virus.

Animals↗
PubMed1982

Features of T cells causing H-2-restricted lethal graft-vs.-host disease across minor histocompatibility barriers.

Evidence is presented that T cells that produce lethal graft-vs.-host disease (GVHD) to minor histocompatibility antigens (minor HA) comprise discrete subgroups of H-2K- and H-2D-restricted T cells; double negative selection of T cells in irradiated H-2 recombinant mice was used to separate these two subgroups. No evidence could be found that I-restricted T cells contributed to GVHD, either as effector cells or helper cells. The (unprimed) precursor cells for GVHD expressed the Thy-1+, Lyt-1+/-2, Ia- phenotype. Studies in which H-2-semiallogeneic bone marrow chimeras were used as hosts for negative selection suggested that presentation of minor HA to T cells during the induction phase is controlled by marrow-derived cells; indirect evidence was obtained that these latter cells can "process" minor HA presented on H-2 different cells and thereby render the antigens immunogenic. Studies in which minor HA-different, H-2-compatible chimeras were re-irradiated and then injected with donor-vs.-host T cells suggested that the effector phase of lethal GVHD involves contact of antigen on non-marrow-derived cells.

Animals↗
PubMed1982

Sequential analysis of the virus-immune responder characteristics of thymocytes from F1 leads to parent radiation chimeras.

The virus-immune responder characteristics of thymocytes, spleen and lymph node (LN) cells from (P1 X P2)F1 leads to P1 radiation chimeras have been examined sequentially at weekly intervals. Adoptively-transferred thymocytes generate strong cytotoxic thymus-derived lymphocyte (CTL) responses from 28 to 100 days after reconstitution with bone marrow, which are almost invariably restricted to recognition of virus presented in the context of P1. This pattern of H-2 restriction is also maintained for spleen and LN cells from the [(H-2kXd)F1 leads to H-2k] and [(H-2kXb)F1 leads to H-2k] combinations but there is random emergence of reactivity to H-2k+virus for peripheral lymphoid cells from [(H-2KkXb)F1 leads to H-2b] chimeras. Treatment of established [(P1 X P2)F1 leads to P1] chimeras with a low dose of cyclophosphamide (Cy) did not lead to the emergence of significant CTL effector function for P2 + virus. Also, administration of a large dose of Cy prior to irradiation of the chimera recipients did not modify the H-2 restriction profile of the chimera, though the level of CTL responsiveness associated with the appropriate H-2 type was apparently enhanced.

Animals↗
PubMed1981

Factors influencing the vaccinia-specific cytotoxic response of thymocytes from normal and chimeric mice.

Following adoptive transfer into irradiated recipients, thymocytes can be induced to respond strongly to vaccinia virus. High levels of cytotoxic T-lymphocyte (CTL) activity may be generated from thymus, but not from spleen, of 3-day-old mice. The capacity of thymocytes to differentiate into effector CTL tends to be lost with age. Some of this loss may reflect positive suppression: a single, low dose of cyclophosphamide allows the reemergence of responsiveness in at least one mouse strain. Thymocytes from [A leads to (A x B)F1] and [(A x B)F1 leads to A] chimeras show the response patterns that would by predicted from previous studies of lymph node and spleen cells. However, thymic function seems to be rapidly lost in the [A leads to (A x B)F1] Chimeras.

Aging↗
PubMed1981

Early dominance of irradiated host cells in the responder profiles of thymocytes from P leads to F1 radiation chimeras.

The number of cells in the thymus of [k leads to (b X k)F1] radiation (100 rad) chimeras increases approximately 10-fold between 7 and 14 days after reconstitution with bone marrow. At least 50% of the cells in thymus on day 14 are of host origin and respond to virus presented in the context of both H-2k and H-2b when primed in irradiated, virus-infected (b X k)F1 recipients. Strong CTL responses can be generated from thymocytes of donor origin on day 21. All evidence of a significant host thymocyte component has disappeared by day 28. The responsiveness of 14-day thymocytes is not abrogated by pretreatment of the mice used to make the chimeras with anti-thymocyte serum or by using doses of irradiation as high as 1200 rads to eliminate host components.

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