摘要:

Thy-1+cell depletion with anti-Thy-1.2 mAb and complement markedly reduced the capacity of C57BL/6J, H-2bbone marrow to establish mixed lymphoid chimerism and induce tolerance to C57BL/6J skin grafts across an entire MHC disparity in BALB/c, H-2dhosts conditioned with sublethal, fractionated 7.5 Gy total-body irradiation. In this model tolerance can be transferred to secondary irradiated BALB/c hosts only by cells of C57BL/6J donor, not host, genotype isolated from the spleens of tolerant hosts. Thy-1+cell depletion abolished the capacity of C57BL/6J donor cells from tolerant BALB/c host spleens to transfer tolerance. The capacity of semiallogeneic BALB/c×C57BL/6J F1, H-2d/bdonor BM and spleen cells to induce chimerism and tolerance to C57BL/6J skin grafts in BALB/c parental hosts was also reduced by Thy-1+cell depletion. Thus the requirement for donor Thy-1+cells cannot be explained simply on the basis of alloaggression. It is unlikely that the requisite Thy-1+cells are nonspecific suppressor cells: Thy-1+cell depletion had no effect on the slight but significant prolongation of third-party C3H/HeJ, H-2kskin grafts in irradiated BALB/c hosts injected with allogeneic C57BL/6J or semiallogeneic BALB/c×C57BL/6J F1BM compared to irradiated controls injected with medium only. Furthermore, injections of semiallogeneic F1spleen cells had no significant effect on the survival of the third-party grafts, although these cells were fully capable of inducing tolerance, and their capacity to induce tolerance was significantly reduced by Thy-1+cell depletion. The requirement for a specific population of lymphoid cells, i.e. Thy-1+, remains unexplained but suggests that donor cells might play a role in the induction or maintenance of tolerance in this model other than merely providing a circulating source of donor antigens.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

In the present study methods are described to obtain both graft infiltrating cells (GIC) of host origin and proximal tubular epithelial cells (PTEC) of donor origin simultaneously from biopsy material of renal allografts undergoing rejection. The identity of PTEC cultures was established using monoclonal antibodies. GIC were shown to exhibit T cell functional activity. These GIC were shown to lyse trypsinized PTEC as well as PTEC monolayers grown from the corresponding biopsy, and not PTEC isolated from biopsies obtained from other patients. Therefore the lytic activity appeared to be donor-specific. Major histocompatibility complex class I antigens were involved since donor PHA-blasts, a target population well known to express class I molecules, were lysed by GIC, and the anti-class I MoAb W6/32 blocked cytolytic activity of GIC against donor PHA-blasts and against donor PTEC.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Culture of thymus tissue in 2-deoxyguanosine (2dGua) is thought to reduce tissue immunogenicity by selectively depleting highly immunogenic, thymic migrants of bone marrow origin. In the mouse 2dGua-treated thymus tissue survival is markedly enhanced compared with untreated tissue when transplanted under the kidney capsule of allogeneic recipients. These experiments were repeated in a rat model. As expected, DA strain neonatal thymus tissue was rejected when transplanted under the kidney capsule of normal allogeneic strain PVG rats. Surprisingly, acute rejection occurred when the tissue was cultured in 4 mM 2dGua, a dose capable of destroying rat thymocytes in vitro and 3 times the effective dose in mice. To test whether residual marrowderived cells that escaped 2dGua treatment were responsible for inducing rejection, the treated DA tissue was “parked” in T cell—depleted PVG rats. Our working hypothesis was that the few remaining donor-derived cells of marrow origin would be overgrown by host-type cells. When 2dGua-treated DA thymus tissue was transplanted into T cell—depleted PVG recipients rejection did not occur. However this DA tissue, parked for as long as 200 days in T cell—depleted rats, was acutely rejected when retransplanted into normal PVG recipients. These results suggest that rat thymic epithelium devoid of marrow-derived cells is innately immunogenic.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

We have made a detailed analysis of the fate of Langerhans cell—free cultured keratinocyte allografts in two rat strain combinations, DA-to-PVG and DA-to-LEW, and compared the results with the rejection of conventional skin allografts in these strain combinations. The cultured keratinocyte layers were grafted both to the body surface using a technique to prevent wound contraction, and to the renal subcapsular site. Histological examination of grafts was made on days 2, 7, 10, 14, and 28 after transplantation. Donor-specific anti—class I MHC monoclonal antibodies were used to verify the donor origin of the keratinocytes. We report that the keratinocyte allografts are acutely rejected—but, in contrast to the conventional allografts, do not evoke alloantibody responses. Rejection of the keratinocytes at the renal subcapsular site was as rapid as that of conventional skin grafts. However, rejection of keratinocyte grafts on the body surface was delayed by a few days when compared with conventional skin grafts. Immunosuppression with cyclosporine prevented the rejection of DA keratinocyte layers placed at the renal subcapsular site of PVG rats, but rejection followed soon after cessation of cyclosporine therapy. These data sugest that rejection is a major constraint for the clinical application of cultured keratinocytes, and that autografts must be used if permanent cover is required. Moreover, the findings have interesting theoretical implications relating to the much greater vulnerability to rejection of skin grafts compared with organ grafts. Out current and previous data also suggest that class II-positive dendritic cells are the major stimulus to alloantibody production afte tissue transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The central nervous system toxicity of cyclosporine, which is known to be neurotoxic clinically, was investigated in a rat model. Munich-Wistar rats were divided into 3 groups for a 2-week protocol. After baseline EEG and behavioral testing, group 1 (control) received a weight-adjusted volume of parenteral cyclosporine vehicle i.p., group 2 (low-dose) received 5 or 10 mg/kg/day i.p., and group 3 (high-dose) received 20 mg/kg/day i.p., Spontaneous behavior was observed, simple sensorimotor testing performed daily, and awake EEG's recorded 3 times per week. Four of 12 high-dose animals died during study, one after a witnessed tonic-clonic seizure, and two after recording of frankly epileptiform EEG's; there were no deaths in control or low-dose animals. Significant EEG abnormalities developed only at high-dose, with frankly epileptiform EEG's and/or seizures seen in 58±15% of these rats (P=0.005, different from controls by life-table analysis). Although some high-dose animals demonstrated hyperirritability and dystonic posturing, behavioral changes were subtle, and animals were often still or rocking slightly during recording of frankly epileptiform EEG's. Walking latency and alley escape behaviors were delayed in high-dose rats, the latter correlating with abnormal EEG's. Serum urea nitrogens were mildly elevated in high-dose animals, but serum creatinine, electrolytes, bilirubin, body magnesium stores, and blood pressure remained normal in all groups. Kidneys showed only mild vacuolation histologically. The brain showed only very focal cortical injury sites related to electrode placement, which did not correlate with EEG changes or mortality. These results suggest that there may be a direct effect of cyclosporine on the central nervous system. This model system should prove useful in defining mechanisms of cyclosporine-related neurotoxicity.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Proximal (LLC-PK1) and distal (MDCK) renal epithelial cell cultures were used to investigate early biochemical changes in cellular metabolism following exposure to cyclosporine A (CsA).3H-thymidine and3H-leucine incorporation into the cells were used as indices of DNA and protein synthesis. The cells were exposed to concentrations of CsA ranging from 0.2 μg/ml to 20 μg/ml. By 20 hr there was a decrease in the total cell count at concentrations of 10 and 20 μg/ml that was more pronounced by 5 days of exposure. At 5 days there was also a reduction in cell count at the lower concentrations of CsA. There was an initial increase in DNA and protein synthesis at 2 hr with inhibition of DNA synthesis evident by 20 hr. Protein synthesis was increased in the LLC-PK1cells and decreased in the MDCK cells. At 5 days there was evidence of increased DNA and protein synthesis, most marked in the remaining viable cells exposed to the higher concentrations of CsA. Similar alterations in cellular metabolism were evident when the cells were exposed to the immunologically inert cyclosporine H (D-N-MeVal11-Cs). These studies demonstrate that cyclosporine produces alterations in cellular function as early as 2 hr after exposure to the drug. At the lower concentrations there is evidence of sublethal cellular toxicity and cellular regeneration. The toxicity appears to be related to the molecular structure of cyclosporine and its incorporation into cell membrances. We postulate that cyclosporine nephrotoxiciy is the summation of several subtoxic alterations in cellular function the final expression of which is modified by other factors affecting renal function.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Polymyositis and myasthenia gravis-like syndromes have been seen in patients with GVH disease following bone marrow transplantation. We therefore investigated the histopathology of muscle in mice with acute graft-versus-host disease in order to determine whether these conditions are caused by injury from the GVH reaction itself or are due to radiation and drugs used to prepare the host for transplantation. GVH reactions were induced by intravenously infusing 50×506lymph node and spleen cells from A/J-strain donors into (C57BL/6×A/J)F1-hybrid recipients. These mice developed an active inflammatory myopathy beginning 15 days after engraftment. The inflammatory infiltrates were focal in distribution, initially around perimysial blood vessels, and later around muscle fibers. The infiltrating cell population was composed of lymphocytes, plasmacytoid cells, and macrophages. Muscle cell necrosis was observed and was temporally related to elevations in serum creatine kinase. Similar histologic changes were present in the myocardium. Our findings support the notion that muscle involvement in patients with GVH disease is caused by the disease itself. Myositis accompanying experimental GVH disease in mice may hold promise as a model of autoimmune inflammatory myopathy.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

C.B-20 (Ighb) but not BALB/c (Ighb) mice are able to reject BCL1, a spontaneous B cell leukemia of BALB/c origin. The protective immune response is directed to ward the minor histocompatibility (H) antigen, H-40, which can be detected by cytotoxic T lymphocytes and is expressed on surface (s) immunoglobulin positive tumor cells including BCL1as well as sIg+lymphoblasts activated by lipopolysaccharide. The fact that only sIg+tumor cells and lymphoblasts express H-40 suggests that sIg itself may be a component involved in CTL recognition of this antigen. However, this possibility was ruled out by demonstrating that removal of sIg from target cells did not prevent H-40-specific CTL recognition. To determine whether H-40 expression was coordinately regulated with that of membrane Ig, we determined whether H-40−sIg−cells acquire H-40 when induced to express sIg. We also transfected a functionalcandvregion gene into a sIg−lymphoma so that it acquired a slg+phenotype. In neither case did such slg+cells acquire H-40. Together, these data indicate that H-40 is expressed on B cells representing a particular stage of differentiation that is coincidental with slg.We previously showed thatH-40andIghloci are linked on the 12th murine chromosome. In this study we further localizedH-40to a point beyondAat(formerlyPre-1) nearLm-1, a locus previously described to encode minor H-antigens expressed on lymphomyeloid cells. Thus,H-401and Lm-1 may represent a gene cluster encoding antigens expressed on subsets of lymphoid and myeloid cells.

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:1989

数据来源: OVID