UMLS:C0018133 - FACTA Search

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Query: UMLS:C0018133 (graft-versus-host disease)
18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inbred strains of rats were used to analyze unidirectional host-versus-graft disease (transplant rejection) without graft-versus-host disease in small intestinal transplants and the immunosuppressive properties of cyclosporine (CsA). Forty-six Lewis rats received heterotopic transplants of the entire small bowel in four groups: Lewis-to-Lewis isografts, without CsA; Lewis-to-Lewis isografts, with CsA (15 mg/kg/day); (Lewis X ACI)F1-to-Lewis allografts, without CsA; (Lewis X ACI)F1-to-Lewis allografts, with CsA. Small bowel rejection was associated with gross morphological changes that preceded all other findings. A histologic scoring system assessed the degree of transplant rejection. A characteristic transient weight loss was seen in animals rejecting their bowels. Glucose absorption was impaired and polyethylene glycol absorption increased during rejection. Cyclosporine inhibited all of these changes in allografted rats. It is concluded that daily administration of cyclosporine is effective in preventing the morphologic and functional changes of acute transplant rejection in intestinal allografts and does not change these parameters in transplants that are not rejecting.
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PMID:Transplantation of the entire small bowel in inbred rats using cyclosporine. 357 68

We have shown that donor-specific unresponsiveness to cardiac and islet allografts can be induced by intrathymic (IT) inoculation of uv-B-irradiated spleen cells or resting T-cells in the Lewis-to-ACI rat combination. To examine if tolerance to cardiac and small intestinal allografts can be induced in adult animals, we employed intrathymic inoculation of resting donor T-cells combined with sublethal total body irradiation of 200 rads on Day -7 relative to organ transplant and consistently induced permanent donor-specific cardiac allograft survival (> 300 days) and small bowel transplant (SBT) survival (> 100 days) in the Lewis-to-ACI rat combination. Similarly, IT inoculation of T-cells on Day -7 combined with 1 ml ALS on Days -7 and 0 relative to SBT resulted in indefinite donor-specific graft survival (> 100 days) in all recipients without any evidence of graft-versus-host disease (GVHD) in the high responder of Wistar-Furth (WF)-to-Lewis rat combination. In contrast, WF SBT was promptly rejected in recipients pretreated with intravenous administration of donor T-cells and ALS, thus confirming the privileged position of the thymus in the induction of tolerance. The long-term unresponsive ACI recipients challenged 150 days after cardiac transplant with a second-set graft specifically and permanently (> 120 days) accepted the second-set SBT without rejecting the primary cardiac grafts and without developing GVHD. Third-party grafts were rejected in a normal fashion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Induction of donor-specific tolerance to rat cardiac and small bowel allografts by intrathymic inoculation of donor T-cells. 833 31

The initial clinical experience with simultaneous small bowel/liver transplantation (SBL) suggests that liver grafting may protect the small bowel from rejection. A pilot study of SBL in DA (RT1a) rats with Lewis (RT1l) allografts in our laboratory provided experimental support for this concept. However, the clinical applicability of the data was questioned because the transplants were performed in a low-immune-responder rat strain combination. This study examined the outcome of SBL in several rat strain combinations. Isolated small bowel transplants (SB) and SBL were performed in three groups: DA-->PVG (low immune responder), BN-->LEW (intermediate immune responder) and ACI-->LEW (high immune responder). Lewis-->Lewis isografts were used as controls. All of the rats with SB rejected their allografts, whereas all of the rats with simultaneous liver grafts had minimal or no signs of intestinal rejection. The outcome of SBL was profoundly affected by the donor-recipient strain combination. The low immune responders developed severe graft-versus-host disease. The intermediate immune responders developed mild-to-moderate GVHD and moderate liver rejection. The high immune responders developed severe liver rejection. In this study, the outcome of small bowel transplantation depended upon the strain combination used and whether or not a simultaneous liver graft was transplanted. The immune interactions that occur after multi-visceral transplantation are complex and cannot be easily predicted.
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PMID:The effect of donor-recipient strain combination on rejection and graft-versus-host disease after small bowel/liver transplantation in the rat. 835 94

UV-B irradiation (700 J/m2) of bone marrow cells (BMC) before transplantation into lethally irradiated (1050R) allogeneic rats prevents graft-versus-host disease (GVHD) and results in stable chimerism. This study examined whether UV-B modulation of BMT is useful in the subsequent induction of tolerance to small bowel transplant (SBT) and avoids the danger of GVHD, which remains the major obstacle to successful SBT. Lethally irradiated Lewis recipients of UV-B irradiated (700 J/m2) BMT (10(8) BMC admixed with 5 x 10(6) splenic leukocytes) either from ACI or Wistar-Furth (WF) rats developed stable chimerism without any evidence of GVHD for > 360 days. Lewis recipients of UV-B ACI BMC expressed 95 +/- 6% ACI lymphoid cells at 50 and 150 days after BMT using complement-dependent cytotoxicity assay. Unmodified Lewis recipients of orthotopic ACI SBT rejected their grafts and died in 7-9 days, whereas Lewis chimeras accepted permanently (> 200 days) bone marrow donor (ACI) SBT without any evidence of GVHD when the SBT was performed at 60 or 150 days after BMT. In contrast, when SBT was performed, only 30 days after induction of chimerism with UV-B ACI BMT, the recipients developed severe GVHD and died between 17 and 21 days. The Lewis chimeras rejected third part (WF) SBT acutely and died in 7-9 days, thus demonstrating the specificity of the induction of tolerance in this model. That this immunologic unresponsiveness is not restricted by the recipient-donor rat strain combination was shown by the permanent acceptance of WF SBT without GVHD by Lewis/WF chimeric recipients. Furthermore, the Lewis chimeras that were made diabetic with STZ 28 days after BMT permanently accepted (> 300 days) BM donor-type (WF) and recipient-type (Lewis) islet cells and became normoglycemic, thus indicating tolerance to both donor and recipient Ags. The diabetic Lewis chimeras that became normoglycemic permanently accepted (> 200 days) WF SBT without any evidence of GVHD after donor-type SBT 110 days after WF islet transplantation. The apparent lack of organ-specific unresponsiveness in this model confirmed our previous observation with combined islet and heart transplants. In vitro MLR studies showed that the chimeric animals were specifically unreactive to donor- and recipient-type alloantigens. Our results demonstrate that UV-B irradiation of BMT is a promising approach to the induction of tolerance to SBT.
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PMID:Prevention of graft-versus-host disease in rat small bowel transplantation by recipient pretreatment with UV-B-modulated bone marrow cells. 851 7

One-hundred and fourteen limb transplantations have been performed across a major histoincompatibility barrier between donor ACI (RT1a) and recipient Lewis (RT1l) rats immunosuppressed with various dosages of FK-506 and cyclosporine. Three-hundred and thirty biopsy specimens from 64 animals have been evaluated histologically for signs of rejection. A new histologic grading system is introduced to classify the process of rejection in the component tissues (skin, muscle, bone, and articular cartilage) of a limb allograft. The results indicate that FK-506 is a more potent immunosuppressive agent than cyclosporine in preventing the rejection of the skin component of a limb transplant. With twice-weekly intermittent immunosuppression with FK-506, the rejection of muscle, bone, and cartilage can be prevented for an indefinite time, although all long-term surviving animals died at around 300 days, probably of graft-versus-host disease. Based on the histologic stages of rejection in the different tissues at the same point in time, it is evident that each component tissue of a limb transplant rejects over a different time period. This probably reflects a hierarchy of antigenicity, with skin being most antigenic, muscle being intermediate in antigenicity, and bone and cartilage being least antigenic. Although this grading system is not the ultimate solution, it may allow a more objective comparison of experimental limb transplantation in the future.
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PMID:Rejection of the component tissues of limb allografts in rats immunosuppressed with FK-506 and cyclosporine. 853 72

We have previously demonstrated that Ultraviolet B (UVB) irradiation of Lewis donor bone marrow (BM) allografts prevents graft versus host disease (GVHD) in ACI recipients while allowing full engraftment. In a one-way GVHD model of parent to Lewis X BN (F1) rats, the site and mechanism of the action of UVB irradiation was assessed by adding nonirradiated isolated cell subsets, isolated by monoclonal antibodies (Mab) to cell surface markers, to the reconstituting UVB-irradiated bone marrow inoculum. GVHD was assessed primarily on clinical grounds by observation of posture, alopecia, skin erythema, and weight loss. The addition of nonirradiated spleen cells or non-UVB-irradiated T-cell subsets (both CD4 and CD8 positive) to the otherwise UVB-irradiated donor inoculum consistently resulted in acute GVHD. In contrast, UVB irradiation of these cells resulted in full engraftment without acute GVHD. Mixed lymphocyte culture (MLC) assays confirmed responsiveness by BM transplanted hosts to third party stimulators while coculture assays failed to show any in vitro suppressor activity in the host. We conclude that UVB acts on both the T-lymphocyte and antigen presenting cell (APC) subsets to prevent acute GVHD. We also propose a model to explain tolerance based on clonal anergy produced by modified antigen presentation by UVB-irradiated APC's or by a modified response to processed antigen.
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PMID:The mechanism of UVB prevention of graft versus host disease. 859 4

PGG-glucan is an immunomodulator which can enhance the host response to infection. Phase I/II clinical trials have documented the safety and potential efficacy of this compound to reduce postoperative infectious complications in high risk surgical patients. Organ transplant recipients may benefit from this drug due to their high rates of postoperative infectious complications. A rat cardiac rejection model (ACI --> Lew) and a mouse skin graft model (C3H/HeJ --> B6AF1/J) were used with four treatment arms (control, Cyclosporine A (CsA), antilymphocyte serum (ALS), and CsA + ALS with and without PGG-glucan). Small intestinal allografts (Lew --> LBNF1) were performed in rats to evaluate GVHD. In the mouse GVHD model, donor splenocytes were given to irradiated recipients (C57BL/6 --> B6AF1), with and without PGG-glucan treatment. There was no difference in survival between PGG-glucan treatment and placebo for the control, CsA, and CsA + ALS groups in rat cardiac recipients. Recipients receiving ALS and treated with PGG-glucan survived a median of 42.5 days versus 63.5 days for those ALS-treated animals not receiving PGG-glucan (P = 0.045). In the remaining groups there was no difference in survival between PGG-glucan-treated groups and the control groups. PGG-glucan did not shorten survival in three of four treatment groups in the rat cardiac rejection model. High dose ALS with PGG-glucan did result in a marginal decrease in survival in cardiac allograft recipients. If the one outlying animal with indefinite survival is excluded, the difference is not statistically significant (P = 0.098). These results show that even though PGG-glucan has immunostimulatory properties, it does not significantly potentiate rejection or GVHD in these animal models. This preliminary work may be important in determining whether PGG-glucan can be safely given to immunosuppressed organ transplant recipients to reduce postoperative infectious complications.
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PMID:PGG-glucan, a leukocyte-specific immunostimulant, does not potentiate GVHD or allograft rejection. 863 36

We studied the modifications of blood T cell distribution following small-bowel allografting in rats under different experimental conditions. Group 1: ACI (RT1a) rats were used as small-bowel donors for ACI x Wistar (RT1y) F1 hybrid rats (WAF1) in which graft-versus-host disease (GVHD) developed. Group 2: WAF1 rats were used as small-bowel donors to ACI rats which developed rejection. Group 3: WAF1 rats received small bowel from ACI rats hyperimmunized for 10 days (by grafting them with WAF1 skin) and GVHD developed. Group 4: Wistar rats received small bowel from ACI rats hyperimmunized for 10 days (by Wistar skin) and bidirectional GVHD and rejection were assured. A second set of the same groups which were continuously administered with cyclosporine (15 mg/kg per day s.c. for 15 consecutive days) was also studied. Recipient peripheral blood lymphocytes, obtained at 7 and 15 days following small-bowel transplantation, were stained with monoclonal antibodies anti-rat CD4 and CD8 and then analyzed in an automated flow cytometer. A significant major reduction of CD4+/CD8+ T cell ratios was shown in rats that developed simultaneous GVHD and rejection with respect to ungrafted rats.
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PMID:CD4+ and CD8+ T cell subset distribution in the blood of small-bowel-grafted rats: modification during graft-versus-host disease. 966 40

Development of partial conditioning strategies to achieve reliable engraftment of allogeneic bone marrow with minimum recipient morbidity could extend the therapeutic application of bone marrow transplantation (BMT) to enzyme deficiency states, hemoglobinopathies, autoimmune diseases, and the induction of tolerance for solid organ and cellular allografts. In this study we describe a nonmyeloablative rat BMT model and examine the effect of clinically available immunosuppressants on the minimum amount of total body irradiation (TBI) required for allogeneic engraftment. Donor ACI marrow was depleted of T cells using immunomagnetic beads and transplanted to major histocompatibility complex- and minor antigen-mismatched Wistar Furth (WF) rats (ACI --> WF) conditioned with varying doses of TBI. Recipients conditioned with TBI alone required myeloablation with 1000 cGy for reliable allogeneic marrow engraftment. Administration to WF recipients of a single dose of anti-lymphocyte serum (ALS) 5 days prior to BMT together with a limited course of tacrolimus (1 mg/kg/day) resulted in engraftment of ACI bone marrow at only 500 cGy TBI. ACI --> WF recipients were stable mixed chimeras (mean donor chimerism 49% at 330 days post-BMT). Chimerism was multilineage. All recipient animals were free of graft-versus-host disease. These results suggest that a nonmyeloablative conditioning strategy based on low-dose TBI and a limited course of tacrolimus plus ALS can produce long-term mixed multilineage chimerism.
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PMID:A partial conditioning strategy for achieving mixed chimerism in the rat: tacrolimus and anti-lymphocyte serum substantially reduce the minimum radiation dose for engraftment. 972 27

The induction of tolerance to organ allografts would eliminate acute and chronic rejection as well as the need for nonspecific immunosuppression. We have shown that tolerance induced through the creation of mixed allogeneic bone marrow chimeras allows for the long-term engraftment of cardiac and small bowel allografts across strong multiple major histocompatibility barriers. The possibility that tolerance might render the host susceptible to graft-versus-host disease (GVHD) has not been investigated in this or other models of tolerance. To test this possibility chimeras were created by transplantation of T-cell depleted ACI and Lewis bone marrow into lethally irradiated Lewis rats. Chimerism was determined post bone marrow transplant (BMTx) by flow cytometry of lymphocytes from reconstituted animals. ACI/Lew chimeras (ALC), Lewis/ACI F1 (LACF1), and Lewis (LEW) rats all received heterotopic ACI vascularized small bowel grafts. A second group of chimeras received small bowel grafts from ACI rats pretreated with low dose irradiation to eliminate T-cells from the graft. LEW-->LEW small bowel isografts were also performed. Animals were examined for evidence of GVHD by clinical signs and histologic examination of biopsied tissues. GVHD was quantified using the popliteal lymph node enlargement assay. All LACF1 rats developed severe lethal GVHD following ACI small bowel transplant. Bone marrow chimeras, ALC (n = 6), developed fatal GVHD in a similar fashion after receiving a small bowel transplant. LEW-->LEW isografts and chimeras receiving bowel from irradiated ACI rats survived long term without GVHD while ACI-->LEW allogeneic transplants all underwent acute rejection. GVHD or its absence was confirmed histologically. Popliteal lymph node enlargement indices reflected the presence of GVHD in the chimeras (1.87) and LACF1 (5.4) receiving allografts, but not in isografts or chimeras receiving irradiated allogeneic transplants. Analysis of cytokines in the tongues of rats undergoing GVHD showed elaboration of Th1 type proinflammatory cytokines which was not seen in isografted rats or rats receiving preirradiated small bowel. These results demonstrate that tolerance induction through mixed chimerism results in susceptibility to small bowel induced GVHD. Preirradiating the donor bowel prior to SBTx can prevent GVHD.
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PMID:Tolerance induction permits the development of graft-versus-host disease: donor-mediated attack following small bowel transplantation in mixed chimeras. 1037 74

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