Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Small amounts of donor strain ACI blood injected in conjunction with minimal ALS therapy prolonged islet allograft survival in Wistar-Lewis, diabetic recipients from a mean of 8 days in nontransfused rats to a mean of more than 100 days. ACI skin grafts transplanted on long-surviving transplant-improved rats were rejected within 8 days, which suggested that "classical" tolerance was probably not the mechanism responsible for the blood-induced suppression of islet allograft rejection.
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PMID:The effect of donor strain blood and ALS therapy on pancreatic islet allograft survival in the rat. 679 74

Since intrathymic (i.t.) injection of UV-B-irradiated spleen cells (SC) or purified resting allogeneic T cells, but not resting B cells, dendritic cells, or macrophages induces specific tolerance in transiently immunosuppressed recipients, we hypothesized that presentation of donor MHC peptide Ag by the host thymic APCs may convey a tolerogenic signal to the recipient. This study examined if i.t. inoculation of allogeneic soluble Ag obtained from 3 M KCl extracts of purified resting T cells can induce specific tolerance to cardiac allografts in transiently immunomodulated recipients. We have now shown that i.t. inoculation of donor soluble Ag on day -7 combined with 1 ml ALS on days -7 and 0 leads to indefinite WF cardiac allograft survival (> 200 days) in Lewis recipients. This finding was reproducible in sublethally irradiated (200 rads TBI) ACI recipients of i.t. Lewis soluble Ag. In contrast, ACI cardiac allografts were promptly rejected in ALS-treated Lewis recipients of i.t. WF soluble Ag, confirming the donor specificity of such immunologic manipulation. Extrathymic inoculation of WF soluble Ag via the intravenous route in controls failed to prevent normal graft rejection in ALS-treated recipients. The long-term unresponsive recipients specifically and permanently accepted donor-type, second-set cardiac allografts. The observation that thymectomy performed 7 days after i.t. Ag injection led to graft rejection strongly suggests that the early phase of induction of donor-specific tolerance is dependent on the presence of donor alloantigens in the host thymus. This approach may have important clinical therapeutic potential in the induction of transplantation tolerance.
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PMID:Induction of transplantation tolerance to rat cardiac allografts by intrathymic inoculation of allogeneic soluble peptides. 827 28

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

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.
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PMID:Induction of donor-specific tolerance to cardiac but not skin or renal allografts by intrathymic injection of splenocyte alloantigen. 847 63

This study extends the finding that intrathymic (IT) injection of 3M KC1 extracts of T cells induces transplant tolerance to the use of well defined polymorphic MHC class I allopeptides derived from the hypervariable domain of RT1.Au (WF MHC class I). While three of the six synthetic RT1.Au peptides were immunogenic, three others were nonimmunogenic when tested in ACI responders. In our initial studies, we examined the effects of IT injection of a mixture of equal concentrations of the three nonimmunogenic RT1.Au peptides on WF cardiac allograft survival in ACI recipients. The results showed that a single IT injection of 100 and 300 microg class I MHC allopeptides on day -7 relative to cardiac transplant did not significantly prolong graft survival in naive ACI recipients (MST of 9.8, and 12.3 days vs. 10.5 days in controls). In contrast, 600 microg allopeptides injected IT resulted in modest prolongation of graft to an MST of 19.5 days. However, IT injection of 600 microg allopeptides combined with 0.5 ml ALS on day -7 led to permanent acceptance (>200 days) of cardiac allografts in 7/9 ACI recipients compared with survival of 24.2 days in ALS alone treated controls. In contrast, similar treatment led to acute rejection of third party (Lewis) cardiac allografts. Intravenous injection of 600 microg allopeptides combined with ALS did not result in prolonged graft survival (26.8 days). The long-term unresponsive ACI recipients (>100 days) challenged with second-set cardiac grafts accepted permanently donor-type (WF) grafts while rejecting the third party (Lewis) grafts, a finding that confirms acquired systemic tolerance. These findings confirm the role of IT injection of synthetic polymorphic allopeptides in the induction of acquired thymic tolerance and provide the rationale for testing this strategy in large animals and eventually in man.
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PMID:Acquired systemic tolerance to rat cardiac allografts induced by intrathymic inoculation of synthetic polymorphic MHC class I allopeptides. 929 86

Recent studies suggest that the adult immune system can be manipulated by intrathymic (IT) inoculation of donor Ag to accept cardiac and islet allografts in the low responder rat combination of Lewis-to-WF. We have now extended this study to examine the effect of IT inoculation of soluble protein Ag obtained from 3M KCl extracts of resting T cells combined with transient ALS immunosuppression on islet allograft survival in the high responder combination of WF-to-Lewis. We first confirmed the earlier observation that IT injection of 2 mg soluble Ag on day -7 led to permanent islet graft survival (>200 days) in the Lewis-to-WF rat combination without the use of recipient immunosuppression and found this to be true in the Lewis-to-ACI rat combination. In the high responder combination of WF-to-Lewis, unmodified Lewis rats pretreated with IT inoculation of 2 mg soluble Ag acutely rejected WF and BN islet allografts. IT inoculation of donor Ag combined with 1 ml ALS transient immunosuppression on day -7 led to a modest graft prolongation [24.8+/-10.1 days as compared with 15.2+/-3.6 days in ALS only treated controls]. Intrathymic injection of soluble Ag on day -7 combined with 1 ml ALS on days -7 and 0 relative to allografting resulted in 100% permanent islet graft survival (>200 days) compared with an MST of 20.6+/-2.3 days in ALS only-treated controls. Similar treatment led to acute rejection of 3rd party (BN) grafts, thus demonstrating donor-specificity. In addition, extrathymic inoculation of donor Ag in similarly immunosuppressed animals did not result in islet graft prolongation, once again confirming the importance of the thymus in tolerance induction. To examine them for donor-specific tolerance, long-term unresponsive (>120 days) Lewis recipients of renal subcapsular islets underwent nephrectomy of the islet bearing kidneys and were challenged with intraportal donor- or third party-type islets after becoming diabetic. All the nonimmunosuppressed recipients of donor-type (WF) islets became permanently normoglycemic (>100 days) while the third-party (BN) grafts were promptly rejected, with an MST of 10.6 days. These findings confirm that acquired thymic tolerance induced by IT inoculation of soluble protein Ag in the low to moderate responder rat combinations is reproducible in the high responder combination provided that adequate peritransplant immunosuppression is used. This study suggests that acquired thymic tolerance in the rat model is dependent on host responsiveness to alloantigens, MHC differences between the donor-recipient pair, and the use of transient immunosuppression in the high responder recipient. This model may have potential clinical application in the development of strategies for specific transplantation tolerance.
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PMID:Dependence of acquired systemic tolerance to rat islet allografts induced by intrathymic soluble alloantigens on host responsiveness, MHC differences, and transient immunosuppression in the high responder recipient. 902 Mar 31

The toxic dose of irradiation required to achieve stable mixed hematopoietic chimerism is the major limitation to its clinical application in transplantation and other nonmalignant conditions such as hemoglobinopathies. This study examines the additive effect of costimulatory blockage, to our previously described tacrolimus-based conditioning regimen, in further reducing the dose of total-body irradiation to achieve stable mixed chimerism in rats. Fully mismatched, 4- to 6-week-old ACI and Wistar Furth rats were used as donors and recipients, respectively. Recipients were administered CTLA4-Ig 2mg/kg/day (alternate days) in combination with tacrolimus 1 mg/kg/day (daily) from day 0 through day +10, anti-lymphocyte serum 10 mg at day +10 (single dose), and total-body irradiation ranging from 100-600 cGy, prior to bone marrow transplantation (day 0) with 100 x 10(6) of T-cell-depleted bone marrow cells. Levels of donor chimerism were determined over a period of 12 months. The short course of CTLA4-Ig, tacrolimus, and ALS led to dramatic engraftments at reduced doses of irradiation: 100% (5/5) and 93% (13/14) of the animals developed mixed chimerism at 400 cGy and 300 cGy, respectively. At 300 cGy, recipients exhibited durable, multilineage mixed chimerism at 365 days with donor cells ranging from 19-42% (mean 23.4%) with no evidence of graft-vs-host disease. These mixed chimeras exhibited in vitro (mixed lymphocyte reaction) and in vivo (skin grafts) donor-specific tolerance. This study suggests that addition of costimulatory blockade to a tacrolimus-based conditioning regimen reduces the dose of irradiation required to achieve stable multilineage chimerism in rats.
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PMID:Combined host-conditioning with CTLA4-Ig, tacrolimus, anti-lymphocyte serum, and low-dose radiation leads to stable mixed hematopoietic chimerism. 1130 Nov 94