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J A Goss

Publications and source records attributed to J A Goss.

At least 55 records · Page 3Linked to original sources
PubMed1995

Administration of anti-CD4 monoclonal antibody with intrathymic injection of alloantigen results in rat cardiac allograft tolerance.

BACKGROUND: We have previously reported the induction of donor-specific tolerance to cardiac allografts after intrathymic injection of alloantigen with simultaneous administration of antilymphocyte serum treatment to eliminate peripheral T cells. The present study determines whether prolongation of a fully major histocompatibility complex-mismatched cardiac allograft is achieved after a single administration of anti-CD4 monoclonal antibody (MoAb) combined with intrathymic injection of alloantigen. METHODS: Male Buffalo rats were given Lewis splenocytes via the intrathymic or intravenous route in combination with a single administration of anti-CD4 monoclonal antibody (OX-38) or anti-CD8 MoAb (OX-8) or both. Heterotopic cardiac transplantation was performed 21 days after intrathymic alloantigen or MoAb pretreatment or both. Fluorescence-activated cell sorter analysis determined changes in lymphocyte compartment T-cell subsets, and in vitro studies examined recipient cellular reactivity. RESULTS: By 21 days after anti-CD4 MoAb treatment earlier nonspecific immunosuppression had resolved with 80% recovery of peripheral CD4+ T cells and restoration of recipient immunocompetence to allow normal rejection of a cardiac allograft. Combined treatment with intrathymic, but not intravenous, alloantigen plus anti-CD4 MoAb induced donor-specific tolerance to subsequent rat cardiac allografts. However, anti-CD8 MoAb combined with intrathymic alloantigen failed to induce tolerance despite a profound depletion of the CD8+ T-cell subset. CONCLUSIONS: Combined treatment of rats with intrathymic donor alloantigen and a single administration of anti-CD4, but not anti-CD8, MoAb significantly prolongs cardiac allograft survival across a fully major histocompatibility complex mismatched strain combination.

Animals↗
PubMed1994

Immunological tolerance to a defined myelin basic protein antigen administered intrathymically.

To explore the mechanisms responsible for the development of tolerance to allografts after intrathymic (IT) injection of alloantigen, the well-defined model of experimental autoimmune encephalomyelitis (EAE), which mimics the human autoimmune disease multiple sclerosis, was used. This inflammatory neurologic syndrome is initiated by myelin basic protein (MBP)-reactive CD4+ T lymphocytes restricted to self-MHC class II molecules. Naive adult, EAE-susceptible Lewis (RT1(1) rats were treated IT, i.v., or i.p. with a single dose (100 micrograms) of guinea pig-myelin basic protein (GP-MBP 1-176) in PBS plus 1 ml rabbit anti-rat lymphocyte serum i.p. Twenty-one days later, all rats were challenged by intradermal hind footpad injections of 50 micrograms GP-MBP in PBS emulsified in CFA. Only IT, but not i.p. or i.v., administration of GP-MBP plus anti-lymphocyte serum conferred marked resistance to a subsequent systemic challenge of GP-MBP, as demonstrated by the prevention of weight loss and paralysis characteristic of EAE. The IT administration dramatically decreased the size and number of histologic perivascular infiltrates observed per visual field in spinal cord of the tolerant animals and decreased GP-MBP-specific T lymphocyte in vitro proliferation (p < 0.01), whereas proliferation to a nonspecific mitogen (Con A) was not altered. With the addition of rIL-2, the decreased Ag-specific proliferative responses of IT-treated animals increased to control levels. Adoptive transfer of 100 x 10(6) splenocytes from tolerant hosts i.v. to naive syngeneic Lewis rats challenge with 100 micrograms GP-MBP in CFA had no effect on clinical or histologic EAE. Exposure of MBP to maturing thymocytes results in functionally immunounresponsive lymphocytes and prevention of autoimmune EAE.

Animals↗
PubMed1994

Autoregulation by eicosanoids of human Kupffer cell secretory products. A study of interleukin-1, interleukin-6, tumor necrosis factor-alpha, transforming growth factor-beta, and nitric oxide.

OBJECTIVE: Methods employed previously to analyze the secretory behavior of rodent Kupffer cells (KC) were used to examine the human KC's secretory response to lipopolysaccharide (LPS). SUMMARY BACKGROUND DATA: As the resident hepatic macrophage, the KC resides at the interface between the portal and systemic circulations. Consequently, this cell may play an integral role in the immune response to antigens and bacteria in the sinusoid. Study of cytokine production by the KC has relied predominantly on the rat as the source of these cells. Whether human KCs respond similarly to rat KCs after LPS stimulation has been a matter of speculation. METHODS: Kupffer cells obtained from seven human livers were tested under conditions identical to those used to study rat KCs. Kupffer cells rested for 12 hours after isolation were stimulated with LPS (2.5 micrograms/mL). Arginine concentration in the culture medium varied from 0.01 to 1.2 mM. To examine the role of eicosanoids, parallel culture wells received indomethacin (10 microM). Culture supernatants were assayed for interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), prostaglandin E2 (PGE2), and nitric oxide. RESULTS: Similar to the rat KC, LPS-stimulated human KCs released IL-1, IL-6, TNF-alpha, TGF-beta, and PGE2. However, unlike rat KCs, nitric oxide could not be detected, regardless of whether the human KCs were exposed to LPS, interferon-gamma (INF-gamma), or LPS + IFN-gamma. Similar to rat KCs, indomethacin prevented PGE2 release while significantly upregulating TNF-alpha, IL-1, and IL-6, but not TGF-beta, consistent with an autoregulatory control of eicosanoids over proinflammatory cytokines. As has been shown in the rat, physiologic levels of L-arginine (0.01 mM) significantly enhanced LPS-induced PGE2 secretion relative to the response in medium containing standard L-arginine concentration (1.2 mM); however, unlike the rat KC, the human's cytokine response to LPS was not downregulated by this enhanced PGE2 release. CONCLUSIONS: Although many functional features are shared by rat and human KCs, significant differences do exist. Such discrepancies reinforce the need to proceed with caution when generalizing from the results obtained in other species to human physiology.

Adult↗
PubMed1994

Induction of immune unresponsiveness to concordant islet xenografts by intrahepatic preimmunization and transient immunosuppression.

Streptozotocin-induced, diabetic mice (C57BL/6) were preimmunized by injecting 25 low temperature, cultured Wistar-Furth (WF) rat islets into the portal vein, and the recipients received one injection of mouse and rat antilymphocyte sera. 3 wk later, fresh WF islets were transplanted under the kidney capsule of the preimmunized recipients, and normoglycemia was maintained in all 13 recipients for 60 d. Removal of the grafts at 60 d returned the mice to a diabetic state. Transplants of fresh WF islets under the kidney capsule without pretreatment of the recipients had a mean survival time of 16.5 +/- 2.5 d. These findings demonstrate that immune unresponsiveness can be achieved across a concordant, islet xenograft barrier within 3 wk after intrahepatic preimmunization with a small number of donor rat islets and transient immunosuppression with antilymphocyte sera.

Animals↗
PubMed1994

Induction of tolerance to islet xenografts in a concordant rat-to-mouse model.

Induction of tolerance to concordant rat islet xenografts (150 Wistar-Furth [WF] islets) in streptozocin-induced (STZ) diabetic mice (C57BL/6) was determined at three different sites for islet implantation (thymus, kidney capsule, and liver). Islets transplanted into the thymus or kidney capsule were either fresh or cultured at 24 degrees C for 7 days, and the mice received a single injection of either anti-mouse lymphocyte serum (MALS) alone or anti-rat lymphocyte serum (RALS) and MALS. Islets transplanted into the liver via the portal vein were cultured at 24 degrees C for 7 days, and the mice received a single injection of MALS and RALS. To document the induction of tolerance, recipients with islet xenografts surviving > 100 days were made diabetic again by STZ (thymus and liver) or nephrectomy (kidney capsule) and received a second transplant of 150 fresh WF islets in the kidney capsule. Kidney capsule placement of fresh or cultured islets with MALS alone or MALS and RALS did not induce tolerance in a significant number of recipients. The intrathymic transplantation of fresh or cultured islets with MALS alone resulted in prolonged WF islet xenograft survival (mean survival time of 39.7 +/- 7.9 days) but did not result in tolerance, whereas the administration of MALS and RALS with the intrathymic placement of fresh or cultured islets induced tolerance in approximately 50% of the mice. Intrahepatic transplantation of cultured islets with MALS and RALS resulted in tolerance to donor islets in 90% of the recipients. Donor specificity was evaluated by a third major histocompatibility complex-disparate fresh Lewis islet xenograft.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Specific prolongation of allograft survival by a T-cell-receptor-derived peptide.

Allograft rejection results from the specific recognition by host CD8+ T cells of allogeneic major histocompatibility complex (MHC) molecules on the tissue graft. The specificity of this cellular response is determined by the molecular interaction of the T-cell receptor (TCR) on host T cells with the MHC molecule and its bound ligand on the grafted tissue. To better understand the precise manner by which the TCR interacts with the MHC-peptide complex and how to therapeutically intervene, we have studied the allogeneic response to the mouse class I MHC molecule Ld. In this report, the therapeutic potential of a synthetic peptide derived from the TCR V beta 8 variable region that predominates in responses to Ld was tested. This V beta 8-derived peptide was found to dramatically and specifically block the in vivo and in vitro allogeneic response to Ld. Furthermore, this specific blocking is not dependent upon the presence of V beta 8+ effector cells nor does the V beta 8 peptide bind to the Ld ligand binding cleft. We propose that this peptide functions as an antagonist, competing with the native TCR for recognition of the Ld molecule.

Amino Acid Sequence↗
PubMed1993

Major histocompatibility complex-specific prolongation of murine skin and cardiac allograft survival after in vivo depletion of V beta+ T cells.

The preferential usage of certain T cell receptor (TCR) V beta genes has been well established in several major histocompatibility complex (MHC)-restricted immune responses. However, V beta usage among allogeneic responses remains unclear. Because recent findings of ours and others indicate that V beta 8 predominates in certain Ld-restricted, peptide-specific responses, we examined the V beta 8 usage in allogeneic responses to Ld. To selectively recognize the Ld molecule, cells from BALB/c-H-2dm2 (dm2), the Ld-loss mutant mouse, were stimulated in vitro or in vivo with wild-type BALB/c cells. We report here that after the intraperitoneal administration of the anti-V beta 8 monoclonal antibody (mAb) F23.1, peripheral V beta 8 T cells were depleted from dm2 mice. This in vivo depletion abrogated the ability of dm2 splenocytes to mount a primary response to Ld molecules. This abrogation was specific, since the response of V beta 8-depleted dm2 cells to Kb/Db antigens was the same as that of control nondepleted dm2 cells. Furthermore, in vivo depletion of V beta 8 cells was found to cause a dramatic prolongation of Ld-disparate skin grafts (mean survival time [MST] 22.1 +/- 2.1 vs. 10.3 +/- 1.1 d for saline-treated controls, or 10.9 +/- 1.7 d for controls treated with mAb KJ23 to V beta 17). By contrast, V beta 8 depletion had no effect on recipients grafted with haplotype-mismatched skin or single Dk-locus-disparate skin. These findings demonstrate that V beta 8+ T cells predominate in allogeneic response to Ld but not other alloantigens. The effect of V beta 8 depletion was found to be even more dramatic on recipients grafted with Ld-disparate vascularized heart transplants (MST > 100 vs. 8.6 +/- 0.5 d for controls). In total, these findings establish the efficacy of using mAb to the V beta gene family to specifically and significantly enhance the survival of allografts. The implications of detecting V beta 8 usage in both alloreactive or MHC-restricted TCR responses to the same class I molecule are discussed.

Animals↗
PubMed1993

Prolongation of small bowel allografts after intrathymic injection of donor alloantigen and ALS.

The increasing success of clinical small bowel transplantation in recent years has been due largely to improved nonspecific immunosuppression of the recipient, which carries significant morbidity. The induction of donor-specific tolerance would eliminate the risk of long-term immunosuppression while ensuring graft function and survival. We have demonstrated that the intrathymic injection of donor splenocytes with the simultaneous intraperitoneal administration of rabbit anti-rat lymphocyte serum results in indefinite donor-specific cardiac allograft survival in > 85% of recipients. In this study, we further examined the effect of this tolerance induction protocol on the more immunogenic small bowel allograft. Male Buffalo (RT1b) rats were exposed to donor alloantigen by an intrathymic injection of 25 x 10(6) MHC mismatched unfractionated Lewis (RT1(1)) splenocytes. The Buffalo recipients were given 1 ml of rabbit anti-rat lymphocyte serum intra-peritoneally at the time of the donor antigen injection and 21 days later underwent a heterotopic 15-cm Lewis small bowel transplant. Pretransplant intrathymic Lewis alloantigen and anti-rat lymphocyte serum treatment prolonged Lewis small bowel survival by approximately 2.5 times (mean survival time = 18.0 vs 7.0 days for controls, P < 0.05). These small bowel allografts demonstrated pericryptic T cell infiltrates, areas of cryptic necrosis, and a dense submucosal lymphocytic infiltrate, all consistent with acute resection. In contrast to our studies achieving donor-specific cardiac allograft survival, this protocol did not result in indefinite intestinal allograft survival. No Buffalo recipients developed evidence of graft-versus-host disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

MHC class II presenting cells are necessary for the induction of intrathymic tolerance.

OBJECTIVE: This study determined the form of cellular donor MHC alloantigen necessary for the induction of intrathymic tolerance. BACKGROUND: The authors have achieved indefinite donor-specific tolerance, to a fully MHC-disparate rat heterotopic cardiac allograft, after the pretransplant intrathymic injection of unfractionated donor splenocytes and a single injection of rabbit anti-rat lymphocyte serum (ALS), without subsequent immunosuppression. METHODS: Male 4-12-week-old Buffalo (RT1b) rats underwent an intrathymic injection of either fractionated Lewis (RT1(1)) red blood cells (purified by Ficoll gradient) or T lymphocytes (purified by nylon wool column and plastic adherence), both of which express only MHC class I alloantigens, or B lymphocytes, macrophages, and dendritic cells (purified by plastic adherence) which express both MHC class I and class II alloantigens. At the completion of alloantigen injection the Buffalo recipient rats were given 1 ml of ALS intraperitoneally. Twenty-one days later a heterotopic Lewis heart was transplanted. RESULTS: The intrathymic injection of the fractions of Lewis MHC class I and class II expressing B lymphocytes, macrophages, and dendritic cells induced a donor-specific tolerance that resulted in indefinite Lewis cardiac allograft survival (MST > 125 days) in all recipients without further immunosuppression, whereas groups receiving MHC class I expressing red blood cell or T lymphocyte injections plus ALS rejected Lewis cardiac allografts with a MST of 7.3 and 16.5 days, respectively, thus indicating that the MHC class II expressing cell is necessary for the induction of intrathymic tolerance. Buffalo recipients with a long-term surviving Lewis cardiac allograft, after Lewis MHC class II expressing cells were still able to reject a third-party heterotopic ACI (RT1a) cardiac allograft in normal time (MST = 7.0 days), but did not reject a second Lewis cardiac allograft (MST > 100 days). Additionally, the intrathymic injection of MHC class II expressing cells resulted in decreased interleukin-2 (IL-2) production and an 80% decrease in in vitro donor-specific cell mediated cytotoxicity, whereas the cytolytic response to a third party was unaltered. CONCLUSION: Donor MHC class II, and not class I, expressing cells are the cells in donor splenocytes, injected intrathymically, responsible for the development of donor-specific allograft tolerance.

Animals↗
PubMed1993

Induction of donor-specific tolerance to cardiac but not skin or renal allografts by intrathymic injection of splenocyte alloantigen.

We have recently found that donor-specific tolerance to a cardiac allograft can be achieved after the intrathymic (i.t.) injection of donor splenocytes and a single intraperitoneal injection of rabbit antirat lymphocyte serum. The present study evaluated whether the tolerance induced by splenocytes injected i.t. could also prevent the rejection of kidney and skin allografts. Male Buffalo (RT1b) rats were given 25 x 10(6) fully MHC-mismatched unfractionated Lewis (RT1l) splenocytes by i.t. injection plus 1 ml of ALS i.p. and 21 days later underwent a Lewis heterotopic cardiac, orthotopic renal, or skin transplant. Lewis i.t. injection induced a donor-specific tolerance with indefinite cardiac allograft survival (> 153.1 days) in 88% of the recipients without the need for further immunosuppression, while renal and skin allograft survival was prolonged (kidney 14.8 days vs. control 7.8 days; skin 11.6 days vs. control 9.2 days) but were still rejected. Buffalo recipients with a long-surviving Lewis cardiac allograft after Lewis i.t. injection were still able to reject a third-party heterotopic ACI (RT1a) cardiac allograft in normal time (7.0 days), but did not reject a second Lewis cardiac allograft (> 100.0 days). In contrast, however, Buffalo recipients with long-surviving Lewis cardiac allografts did reject a Lewis skin allograft in normal time (10.0 days) and a Lewis renal allograft in a prolonged manner (17.6 days) without causing the rejection of the Lewis cardiac allografts. These data support the important role tissue-specific non-MHC antigens may play in the rejection of kidney and skin allografts.

Animals↗
PubMed1993

Intrathymic injection of donor alloantigens induces specific tolerance to cardiac allografts.

The induction of donor-specific tolerance would eliminate the risk of long-term immunosuppression while ensuring allograft function and survival. Male Buffalo (RT1b) rats were exposed to donor alloantigen by an intrathymic, intrasplenic, s.c., or i.v. injection of 25 x 10(6) syngeneic Buffalo (RT1b) or MHC fully mismatched Lewis (RT1l), ACI (RT1a), or UV-B irradiated Lewis (RT1l) splenocytes. The Buffalo recipients were given 1 cc of rabbit antirat antilymphocyte serum (ALS) i.p. at the time of the donor antigen injection, and 21 days later received a heterotopic Lewis or ACI heart transplant. Only intrathymic alloantigen injection induced a donor-specific tolerance which allowed the cardiac allograft to survive indefinitely (mean survival time [MST] > 176.8 days) in > 86% of the recipients without the need for further immunosuppression, whereas groups receiving antigen injections at other sites rejected cardiac allografts in control time (MST approximately 7.0 days). Histologic examination of long-term tolerated Lewis cardiac allografts revealed the presence of healthy cardiac myocytes without mononuclear infiltration. Buffalo rats with a long-term surviving Lewis cardiac allograft did not reject a second Lewis cardiac allograft (MST > 100.0 days), but rejected a heterotopic ACI cardiac allograft in normal time (MST approximately 7.0 days). By limiting dilution analysis (LDA), maturation of donor-specific CTLs (pCTL) from long-term recipient splenocytes was markedly diminished, whereas third party pCTL was not altered, and T helper-precursors were moderately decreased without alteration in the peripheral CD4+ and CD8+ phenotype frequencies. MLC responses of recipients with long-term surviving cardiac allografts to donor-specific and third party stimulation were not significantly different from naive controls. Microchimerism is unlikely because Lewis allograft survival was also prolonged (MST > 96.0 days) in rats receiving UV-B irradiated Lewis splenocytes which cannot proliferate. The absence of increased allograft survival after transfer of long-term recipient splenocytes into naive animals suggests that donor-specific suppressor cells are not present. Additionally, in vitro lymphocyte proliferative responses to mitogenic or allogeneic stimulation in MLC was not diminished by the addition of these long-term recipient splenocytes. This model emphasizes the importance of exposure of T cell precursors to foreign donor alloantigen in the thymic environment for the development of unresponsiveness to a donor-specific vascularized allograft.

Animals↗
PubMed1993

Prostaglandin E2 downregulates Kupffer cell production of IL-1 and IL-6 during hepatic regeneration.

The mammalian liver possesses the ability to regenerate to its original size after a 70% partial hepatectomy (PHx). The capacity of rat Kupffer cells (KC) isolated at specific intervals after PHx to produce interleukin (IL)-1, IL-6, and prostaglandin E2 (PGE2) in response to endotoxin [lipopolysaccharide (LPS)] stimulation was evaluated in standard RPMI 1640 (1,200 microM L-arginine) and arginine-depleted RPMI 1640 (< 10 microM L-arginine) media. Because KC function in an environment in which high arginase activity results in negligible L-arginine levels, the 10 microM L-arginine RPMI 1640 was used to simulate the hepatic microenvironment. Regenerating liver KC 12-120 h after PHx responded to LPS with a significantly greater (P < 0.05) production of IL-1 and IL-6 in standard RPMI 1640. This enhancement of regenerating liver KC to produce IL-1 and IL-6 was increased (P < 0.05) by placing these same KC in 10 microM arginine RPMI 1640 culture media. During the same time period, regenerating liver KC produced significantly elevated (P < 0.01) PGE2, again with greater differences in the low-arginine media. In vivo KC PGE2 blockade by indomethacin (5 mg/kg) significantly (P < 0.05) inhibited hepatic regeneration. When the cyclooxygenase inhibitor indomethacin (10 microM) was added to cultures, the production of PGE2 by KC was prevented, and in arginine-depleted cultures, IL-1 and IL-6 production was upregulated (P < 0.05). We conclude that during hepatic regeneration, KC IL-1 and IL-6 production is elevated and is controlled in an autoregulatory fashion by elevated KC PGE2 production.

Animals↗