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)

Although chronic immunosuppression has been extremely successful in clinical organ transplantation, it is associated with severe complications such as opportunistic infections, spontaneous neoplasms, drug toxicities, metabolic complications, and the inability to control rejection. We therefore have investigated the ability of allogeneic donor lymphoid cells to produce specific tolerance following intrathymic (IT) injection into allograft recipients. Groups of B6AF1 mice received ALS on days -1 and +2 relative to C3H/He skin grafts on day 0; experimental groups received 1, 5, or 10 x 10(7) syngeneic (B6AF1) or allogeneic (C3H) spleen cells (SPCs) by IT injection on day +7. IT injection of C3H splenocytes significantly prolonged allograft survival at all cell doses tested when compared with ALS controls. The best survival was obtained following IT injection of 5 x 10(7) C3H cells (median survival time [MST] = 132 days; ALS controls = 21.5 days), with 8 of 13 skin grafts surviving longer than 100 days. IT injection of syngeneic splenocytes or third-party DBA/2 splenocytes did not prolong allograft survival beyond that observed in ALS controls. C3H spleen cells injected IT into ALS treated mice on day 0 relative to grafting of C3H skin also produced significant allograft survival (1, 5, or 10 x 10(7) SPCs = MSTs of 75, 47, and 35, respectively) but the results were inferior to those obtained by 5 x 10(7) SPCs IT on day +7. Spleen cells (1 or 5 x 10(7)) injected intraperitoneally or intravenously prolonged allograft survival beyond that seen in ALS controls but were inferior to IT injection at all doses and times studied. Bone marrow, thymocytes, or lymph node cells (5 x 10(7) cells) were substituted for SPCs for IT injection. IT injection of BM, LN or thymocytes all significantly prolonged graft survival over ALS controls. However none of these cell types was as effective as IT splenocytes. Eight B6Af1 recipients of IT splenocytes bearing C3H skin grafts for > 100 days received a second C3H skin graft as well as a simultaneous third-party B10.AKM skin graft. All rejected third-party grafts in normal first-set fashion. Three tolerated both 1st and 2nd C3H grafts without any sign of rejection; 1 rejected the 2nd C3H graft while tolerating the 1st graft; and 4 rejected the 2nd C3H graft in an attenuated fashion but also rejected the 1st graft at the same pace.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Induction of specific unresponsiveness (tolerance) to skin allografts by intrathymic donor-specific splenocyte injection in antilymphocyte serum-treated mice. 146 74

B6AF1 recipients treated with various combinations of ALS, CsA, and BMC were grafted with C3H skin from adult or neonatal donors. A survival advantage of neonatal skin compared with adult skin was clearly demonstrated in groups treated with ALS and CsA (median survival time [MST] = 89 days, neonatal skin; 50 days, adult skin), ALS and BMC, (MST = 92 days, neonatal; 64 days, adult skin), or with ALS only (MST = 55 days and 35 days, respectively). In these groups only neonatal grafts were observed to survive greater than 100 days. Also, once it was underway, rejection of the neonatal skin proceeded more slowly than that of adult skin. ALS/BMC/CsA treatment of adult skin recipients improved graft survival modestly (MST = 77 days, 20% of grafts surviving greater than 100 days). But neonatal graft survival was prolonged remarkably by the ALS/BMC/CsA treatment, with 95% of grafts surviving greater than 100 days and 84% surviving greater than 240 days. After bearing neonatal grafts for greater than 150 days, these mice were challenged with C3H adult skin grafts. The second grafts were uniformly accepted for greater than 135 additional days, but third-party grafts were rejected promptly. This specific tolerance could not be abrogated by injection of normal B6AF1 spleen cells, and rejection of the grafts by adoptively transferred sensitized cells was delayed (MST = 35 days). That the tolerance developed in response to grafting neonatal skin to ALS/BMC/CsA-treated recipients extends to adult tissue suggests that understanding of the immunoregulatory signal provided by the neonatal tissue might lead to a tolerogenic protocol for use with adult allografts.
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PMID:Induction of allograft tolerance with neonatal skin. 203 Dec 61

These studies were designed to determine (1) if culture-isolated, neonatal rat islets are capable of inducing xenogeneic tolerance in mice and (2) whether this tolerance is species- or strain-specific. We attempted to induce xenogeneic tolerance by transplanting culture-isolated neonatal FSH islets to 26 diabetic C57B1/6 recipients. These animals received one injection of ALS at the time of transplant. Fifteen (58%) animals remained reversed by xenotransplant for > 173 days. To assess the development of strain or species-specific tolerance, 14 of the animals bearing long-term surviving FSH grafts were divided into 3 treatment groups. Animals in group 1 were nephrectomized to remove the initial graft and then retransplanted with uncultured, adult FSH islets; animals in group 2 were retransplanted with uncultured, adult FSH islets without nephrectomy; and group 3 animals were nephrectomized and retransplanted with uncultured, adult third-party islets (WF). In naive controls, adult FSH islets were rejected in 9 +/- 2 days. The MST for adult FSH grafts transplanted to nephrectomized recipients was 104 +/- 54 days, with 4 out of 5 (80%) surviving until sacrifice 90-171 days posttransplant. The MST for FSH grafts transplanted to nonnephrectomized recipients was 120 +/- 70 days with 3 out of 4 (75%) surviving until sacrifice 143-154 days posttransplant. Thus, it appears that the initial neonatal FSH transplant induced the development of immune tolerance to highly immunogenic FSH islet tissue. In contrast, the MST for third-party adult WF grafts was 27 +/- 13 days compared with an MST of 36 +/- 24 days in naive controls. Thus, it appears that the xenogeneic tolerance induced by neonatal FSH islets was strain rather than species-specific. Factors such as the close evolutionary relationship between rats and mice, the neonatal condition of the initial graft, and its relative lack of donor APCs are included in a discussion of possible mechanisms of tolerance induction.
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PMID:Long-term survival and strain-specific tolerance induction in rat-to-mouse neonatal islet xenografts. 824 19

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

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that is characterized by the progressive degeneration of both upper motor neurons in the motor cortex and lower motor neurons in the brainstem and spinal cord. Recent advances in human genetics have identified more than 30 ALS-causing genes or genetic loci that include the fused in sarcoma (FUS) gene. In addition, a set of studies suggested a mutual relationship between cancer and ALS. The hpo gene, Drosophila MST was newly identified as a novel genetic modifier of the cabeza (caz), Drosophila FUS. The Hippo pathway negatively regulates the control of organ growth and tumor suppression. Moreover, the p53 tumor suppressor was found to genetically interact with caz. Frontotemporal lobar degeneration (FTLD) is characterized by the degeneration of neurons in the frontal and temporal lobes, and consists of a spectrum with ALS. Fusion protein nucleophosmin-human myeloid leukemia factor 1 (NPM-hMLF1), which is associated with the pathologies of myelodysplastic syndrome and acute myeloid leukemia, was recently shown to suppress defects in the Drosophila FTLD model expressing the human FUS gene. Further studies in the field are expected to elucidate epidemiological, genetic, and histopathological links between cancer and ALS/FTLD, and will lead to the development of therapeutic strategies. We herein summarize previous and current findings that support mutual links between cancer and ALS/FTLD.
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PMID:Cancer-related genes and ALS. 3113 77