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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)

This study tests the hypothesis that small bowel transplantation alters the function of the intestine. The function of the small intestine was investigated after syngeneic (BN----BN or Lew----Lew) and fully allogeneic (BN----Lew) orthotopic total small intestinal transplantation (SIT) using a two-stage model. All animals were treated with cyclosporine A throughout the 60-day study period. Syngeneic transplantation reduced weight gain in the (BN----BN) rats, but not in the (Lew----Lew) animals. Allogeneic transplantation caused a reduction in weight gain for the first 30 days posttransplantation, which may have been associated with graft-versus-host disease. Thereafter, the rate of growth of allogeneic SIT animals was normal. Dietary fat absorption was reduced in all groups of transplanted animals. Intestinal permeability to mannitol and polyethylene glycol 400 (PEG-400) was increased by syngeneic transplantation in all groups, with further permeability increases to mannitol, lactulose, PEG-400, and 51Cr-EDTA after allogeneic SIT. The glucose-stimulated intestinal short circuit current was reduced by both syngeneic and allogeneic SIT, but the maximal active transport rate for glucose uptake was increased, as was the passive uptake of fatty acids. These functional alterations were not associated with changes in intestinal morphology or evidence of rejection. These findings demonstrate that: (1) SIT results in significant changes in the transport characteristics of the bowel, but these have a minimal impact on the well-being of the animal overall; (2) SIT induces an increase in intestinal permeability to mannitol and PEG-400, with a further increase in permeability to all markers following allogeneic SIT; (3) following SIT, and the immune events associated with allogeneic SIT, significant adaptation of the transplanted intestine occurs. We suggest that denervation of the small intestine after SIT is the underlying cause of the changes observed.
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PMID:Intestinal function following allogeneic small intestinal transplantation in the rat. 173 18

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

This study demonstrates that systemic interleukin 2 (IL-2) can decrease the homing of syngeneic immune T cells to the target organ of metastases and accelerate unwanted side effects of allogeneic immune T cells. As a tumor system, we used the well-characterized highly aggressive DBA/2 mouse leukemia ESb and its less aggressive adhesion variant, ESb-MP. Systemic IL-2 treatment was performed with recombinant human interleukin-2 (Proleukin), which was slowly released via an implanted osmotic pump or was modified with polyethylene glycol (PEG-IL-2) to achieve constant plasma levels. Allogeneic B10.D2 antitumor immune spleen cells (ISPL cells) exerted strong graft-versus-leukemia (GvL) reactivity after adoptive transfer into late-stage ESb-MP tumor-bearing DBA/2 mice. Mls(a) superantigen-reactive vbeta6 donor T cells were not eliminated or tolerized by in vivo priming with the tumor cells and were present in active proliferation in liver infiltrates. When exogenous PEG-IL-2 or Proleukin was applied in addition to ISPL cells in such mice, the strong GvL-mediated protective immunity was converted into a fatal graft-versus-host disease. IL-2 treatment alone had no toxic effect and caused a moderate protection effect in the absence of an effect on local tumor growth. Potentiation of GvH reactivity of B10.D2 ISPL by PEG-IL-2 was proven in non-tumor-bearing DBA/2 mice, in which graft-versus-host disease was characterized by: (a) heavy hepatic lymphocytic infiltration, (b) irreversible increase of serum glutamate-oxalacetate-transaminase and glutamate-pyruvate-transaminase levels, (c) weight loss, and (d) death. Antagonistic effects of systemic IL-2 on GvL were observed with syngeneic DBA/2 anti-ESb immune peritoneal effector cells (PECs). There was a detrimental effect of systemic IL-2 on liver target organ infiltration by immune T cells causing, at day 6 after transfer, a drop from 20-30 CD4 or CD8 T cells per liver lobule in the PEC group to <5 in the PEC plus IL-2 group. The results emphasize the importance of a better understanding of IL-2 function in vivo and of its interaction with immune cell function to improve protocols for optimal application in the clinic to achieve maximal GvL effects.
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PMID:Antagonistic effects of systemic interleukin 2 on immune Tcell-mediated graft-versus-leukemia reactivity. 982 26

Immunological recognition of foreign cells is a primary concern in both transfusion and transplantation medicine. Our unique approach to this problem is to globally camouflage the surface of the foreign cell using nonimmunogenic, long chain polymers such as methoxypoly(ethylene glycol) [mPEG]. mPEG-modification of red blood cells effectively attenuates both antibody binding to surface epitopes and decreases the inherent immunogenicity of foreign, even xenogeneic red cells. These cells exhibit normal structural and functional characteristicsin vitro and exhibit normal in vivo survival in animal models. Pegylation of white blood cells (particularly antigen presenting cells and T lymphocytes) surprisingly prevents recognition of foreign class II molecules and prevents T cell proliferation in response to foreign MHC molecules. Potential applications for the covalent binding of nonimmunogenic, long chain polymers (e.g., PEG) to intact cells include, but are not limited to: 1) derivatized RBC to diminish transfusion reactions arising from sensitization to minor blood group antigens (allosensitization) in the chronically transfused (e.g., sickle and thalassemia patients); 2) use of mPEG modification of "passenger" lymphocytes to prevent immune recognition and graft versus host disease; and 3) derivatization of the vascular endothelium of donor tissues prior to transplantation to prevent/diminish acute tissue rejection. In contrast to highly specific blocking mechanisms (e.g., anti-CD4; proteolytic removal of RBC A/B antigens), the generation of globally camouflaged (i.e., stealth) cells may more effectively prevent the often complex and redundant events leading to immune recognition of foreign cells.
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PMID:Cellular camouflage: fooling the immune system with polymers. 1019 54

Transfusion or transplantation of T lymphocytes into an allogeneic recipient can evoke potent immune responses including, in immunocompromised patients, graft-versus-host disease (GVHD). As our previous studies demonstrated attenuated immunorecognition of red blood cells covalently modified with methoxy(polyethylene glycol) (mPEG), we hypothesized that T-cell activation by foreign antigens might similarly be prevented by mPEG modification. Mixed lymphocyte reactions (MLR) using peripheral blood mononuclear cells (PBMC) from HLA class II disparate donors demonstrate that mPEG modification of PBMC effectively inhibits T-cell proliferation (measured by (3)H-thymidine incorporation) in a dose-dependent manner. Even slight derivatization (0.4 mmol/L mPEG per 4 x 10(6) cells) resulted in a >/=75% decrease, while higher concentrations caused >/=96% decrease in proliferation. Loss of PBMC proliferation was not due to either mPEG-induced cytotoxicity, as viability was normal, or cellular anergy, as phytohemagglutinin (PHA)-stimulated mPEG-PBMC demonstrated normal proliferative responses. Addition of exogenous interleukin (IL)-2 also had no proliferative effect, suggesting that the mPEG-modified T cells were not antigen primed. Flow cytometric analysis demonstrates that mPEG-modification dramatically decreases antibody recognition of multiple molecules involved in essential cell:cell interactions, including both T-cell molecules (CD2, CD3, CD4, CD8, CD28, CD11a, CD62L) and antigen-presenting cell (APC) molecules (CD80, CD58, CD62L) likely preventing the initial adhesion and costimulatory events necessary for immune recognition and response.
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PMID:Stealth cells: prevention of major histocompatibility complex class II-mediated T-cell activation by cell surface modification. 1047 44

The small number of studies done on the covalent modification of RBC with PEG, or PEG-derivatives, suggests that the immunocamouflage of intact cells significantly reduces the antigenicity and immunogenicity of the foreign cell. Importantly, this protective immunologic effect can be accomplished without adversely affecting the structure, function, or viability of the modified cell (e.g., RBCs and lymphocytes). As a consequence, PEG-RBC may have significant practical value in the treatment of the chronically transfused patient as a prophylactic measure against allosensitization. The PEG-RBC also may be useful in treating the already allosensitized individual. As shown, preexisting antibodies do not effectively recognize nor bind to the modified donor cells. A finding of further interest to transfusion medicine is that pegylation of contaminating lymphocytes within RBC products may prove efficacious in preventing graft-versus-host disease in the immunocompromised patient. However, the main emphasis of our research continues to be the immunocamouflage of RBC for use in chronic transfusion therapy of the SCD and thalassemic patient.
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PMID:Camouflaged blood cells: low-technology bioengineering for transfusion medicine? 1066 40

Children with severe combined immunodeficiency (SCID) die within 2 years of age if untreated. The only effective treatment for SCID since 1968 is a hematopoetic stem cells (HSC) transplantation. Only 25% of patients have an HLA matched related donor, while the rest have to be transplanted with T cells depleted haploidentical parental bone marrow, unrelated bone marrow or unrelated umbilical cord blood. In many cases, however, despite a positive outcome, children are not achieving B cell reconstitution and require regular IV Ig infusion. Gene therapy with genetically modified autologous cells offers a cure with no immunological complications such as graft rejection, graft versus host disease (GVHD) or post-transplantation immunosuppressive therapy. The first gene therapy trials were introduced in 1990 for adenosine deaminase (ADA) deficient patients who had failed to respond to PEG-ADA. Since then, three clinical trials have evaluated the transplantation of ex-vivo transduced autologous haematopoietic stem cells (HSC) to treat ADA deficiency. One trial used only bone marrow HSC, a second used bone marrow plus peripheral blood T lymphocytes, and a third used umbilical cord blood HSC. These trials give promise but also define the present limitations of gene therapy. Future protocols might be adjusted according to the new observations that ADA-expressing T cells have a strong selective advantage over ADA-deficient T cells. PEG-ADA enzyme therapy might be therefore contraindicated. Another new strategy might involve moderate conditioning prior to the reinfusion of genetically modified CD34+ cells, "making space" for transplanted HSC. The first successful gene therapy was reported for treatment of X-linked severe combined immunodeficiency (SCID-X1) in Science 2000. Since then, the group at the Hopital Necker in Paris has treated 11 patients with ex-vivo gene therapy for the deficiency of the common g chain. All eleven boys are alive, however, one of them recently developed a leukaemia-like disease. This case is being investigated to determine whether the genetic manipulations of the patient's HSC could be the reason for mutagenesis and how other factors could have contributed to this unfortunate event.
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PMID:[Transplantation of genetically modified cells in the treatment of children with SCID: great hopes and recent disappointments]. 1313 Jan 67

Graft-versus-host disease (GVHD) can occur following the transfer of allogeneic lymphocytes into immunosuppressed and, in rare cases, immunocompetent recipients. The initiation of GVHD requires the allorecognition of the recipient's disparate MHC molecules by the donor T lymphocytes (T cell). Currently, GVHD is controlled by cyclosporine administration--a potent, but toxic, T-cell suppressing agent. To determine if the nontoxic grafting of methoxypoly(ethylene glycol) (mPEG) to immunologically foreign lymphocytes could prevent allorecognition and GVHD, in vitro and in vivo murine studies were performed. In vitro studies utilizing mixed lymphocyte reactions (MLRs) demonstrate that mPEG modification effectively prevented allorecognition and subsequent T-cell proliferation. The loss of cellular proliferation was not due to mPEG cytotoxicity but rather to the inhibition of cell-cell interactions. Flow cytometric studies showed that T-cell and antigen-presenting cell adhesion molecules (CD2, CD11a), signaling (CD3epsilon, T-cell receptor), and costimulatory molecules (CD28, CD80) were efficiently immunocamouflaged by mPEG derivatization. Interestingly, upon antigenic stimulation mPEG-modified cells demonstrate enhanced apoptosis as evidenced by DNA laddering. In vivo studies using immunocompetent and immunosuppressed mice established that mPEG modification of donor lymphocytes effectively attenuated the in vivo proliferation of donor cells and the initiation of GVHD.
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PMID:Immunocamouflage: prevention of transfusion-induced graft-versus-host disease via polymer grafting of donor cells. 1456 6

Immunological recognition of allogeneic tissue is of critical concern in transfusion and transplantation medicine. While the major emphasis of our work on the immunocamouflage of cells has been focused on the erythrocyte, we have extended this research beyond the red blood cell (RBC) to other tissues. Our studies from blood transfusion (i.e., a specialized form of cellular transplantation) suggest that covalent modification of cells and tissues with methoxypoly(ethylene glycol) mPEG can significantly diminish immunologic recognition of other allogeneic tissues and, furthermore, may enhance the induction of tolerance. The mechanisms underlying the mPEG-mediated immunocamouflage of alloantigens is the global camouflaging of antigenic sites, membrane surface charge and the attenuation of receptor-ligand and cell-cell interactions. As a consequence of the immunocamouflage imparted by the grafted mPEG, weak costimulation of alloreactive T cells is observed which subsequently induces apoptosis of these reactive cells. As a result of this clonal deletion, a pro-tolerance state is induced. The potency of immunocamouflage is readily observed in in vivo murine models of transfusion-associated graft versus host disease. Furthermore, initial studies on the in vivo transplantation of pegylated rat and murine pancreatic islets have demonstrated that mPEG-derivatization does not impair the finely tuned signaling necessary for glucose homeostasis. Finally, in contrast to the pharmacological inhibition of the immune response by agents such as cyclosporine, mPEG-mediated immunocamouflage directly attenuates the inherent antigenicity and immunogenicity of the donor tissue itself while leaving the recipient a fully competent immune system.
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PMID:Beyond the red cell: pegylation of other blood cells and tissues. 1498 May 48

To explore the effect of bone marrow camouflaged with methoxy polyethylene glycol (mPEG) on allogeneic bone marrow transplantation, 60 BALB/c(H-2d) mice were randomly divided into 3 groups after irradiation by 8.0 Gy of (60)Co gamma ray. A group was given RPMI 1640 0.5 ml in tail vein. B group was infused with the bone marrow cells (1 x 10(7)) mixed with the spleen cells (1 x 10(7)) of donor 615(H-2k) mice. C group was transplanted with same dose cells, which were camouflaged with mPEG before infusion. Severity GVHD was determined by total manifestation of mice, survival rate, survival time and histo-pathological microscopy, and engraftment of allogeneic bone marrow was evaluated by chromosome examination. The results showed that 75% mice in B group had severe adverse manifestations, such as hunched posture, diarrhea and loss of hair. Occurrence of the same adverse manifestations in C group was 35% and significantly lower than that in B group (P <or= 0.05). The mean survival time and survival rate of C group were 16.1 days and 50% respectively, which were higher than those of B group (12.1 days and 20%). White blood cells in peripheral blood of C group mice recovered more quickly than that in B group mice. The number of GVHD grad III in B group was 59%, whereas in C group was 20% (chi(2) = 3.844, P = 0.050); allogeneic bone marrow was successfully engrafted in B and C groups. In conclusion, GVHD of allogeneic bone marrow transplantation can be alleviated by bone marrow cells camouflaged with mPEG, and such transplantation may be able to prolong survival time and increase survival rate.
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PMID:[Study on bone marrow transplantation camouflaged with methoxy polyethylene glycol]. 1597 31


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