Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a fully allogeneic murine combination of C3H/HeSlc (C3H) (H-2k) and C57BL/6CrSlc (B6) (H-2b), C3H mice were primed i.v. with 1 X 10(8) spleen cells from B6 mice preimmunized i.v. with 5 X 10(7) C3H spleen cells and then were given i.p. 200 mg/kg cyclophosphamide (CP) 2 days later (Im-B6-Sc plus CP group). The tolerant state in those recipient mice was compared with that in mice made tolerant conventionally with 1 X 10(8) naive B6 spleen cells plus 200 mg/kg CP (naive-B6-Sc plus CP group). B6 skin was rejected in an almost normal fashion in both the naive-B6-Sc plus CP group and the Im-B6-Sc plus CP group. However, EL4 tumor allografts (B6 origin) inoculated after complete rejection of B6 skin grafts were specifically accepted in both groups. Moreover, the tumor growth in the Im-B6-Sc plus CP group was faster than that in the naive-B6-Sc plus CP group. Mixed lymphocyte reaction, cytotoxic T lymphocyte activity, and antibody production against the tolerogen were depressed more profoundly in the Im-B6-Sc plus CP group than in the naive-B6-Sc plus CP group. These observations were consistent with the results from tumor allografting. The other immunological parameters examined in the present study, including helper T cell activity and delayed foot-pad reaction, were retained in the Im-B6-Sc plus CP group at the same levels as in the naive-B6-Sc plus CP group. These observations were consistent with the results from skin allografting. In conclusion, tumor allograft tolerance was made more profound by the use of spleen cells from donors preimmunized with recipient antigens as the tolerogen than by the use of naive spleen cells. However, skin allograft tolerance was not achieved at all by these same treatments. The contribution of graft-versus-host disease to this phenomenon was excluded by the chimeric analysis in AKR/JSea (H-2k) mice given the preimmunized (with AKR antigens) B6 spleen cells plus CP. These results strongly support the existence of a less proliferative lymphocyte population which does not evoke cell divisions to mature even after the strong stimulation with the preimmunized spleen cells and is resistant to tolerance induction.
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PMID:Drug-induced tolerance to allografts in mice. X. Augmentation of split tolerance in murine combinations disparate at both H-2 and non-H-2 antigens by the use of spleen cells from donors preimmunized with recipient antigens. 330 19

The ability of highly purified CD8+ T cells to mediate GVL activity and facilitate engraftment of allogeneic bone marrow cells was studied in the C57BL/Ka-->BALB/c mouse strain combination. Splenic CD8+ T cells were enriched by depletion of CD4+ T cells by "planning" or purified by positive selection by cell sorting. Although C57BL/Ka bone marrow cells reconstitute lethally irradiated BALB/c mice without severe GVHD, the addition of at least 1.0 x 10(6) donor spleen cells induced uniform acute lethal GVHD. Equivalent doses of spleen cells depleted of CD4+ T cells failed to induce lethal GVHD. Allogeneic bone marrow cells alone failed to mediate antitumor activity against the BCL1 B cell leukemia/lymphoma as compared with syngeneic bone marrow and spleen cell injections. Despite the inability to induce severe GVHD, CD4+ T cell-depleted allogeneic spleen cells prevented the progressive growth of the BCL1 tumor, and eliminated BCL1 idiotype-positive tumor cells in the blood. In order to determine whether CD8+ T cells can prevent tumor growth in the absence of other spleen cell subsets, such as NK cells, that are present in the CD4- populations, highly purified CD8+ T cells were obtained by positive selection using flow cytometry. The latter cells prevented the progressive growth of the tumor, and markedly reduced the level of tumor cells in the blood. Sorted CD8+ T cells facilitated the engraftment of allogeneic marrow cells in sublethally irradiated hosts. Thus, addition of highly purified CD8+ T cells to marrow cells provides GVL activity and facilitates engraftment without inducing severe GVHD in most recipients.
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PMID:The role of purified CD8+ T cells in graft-versus-leukemia activity and engraftment after allogeneic bone marrow transplantation. 765 65

Over the past decade, many studies have suggested that allogeneic blood transfusions (ABT) may adversely affect a recipient. The ABT-associated deleterious effects include the development of transfusion reactions, graft-versus-host disease, alloimmunization, and immunomodulation. While the ABT-associated immunosuppressive effects might be beneficial for recipients of kidney allografts, in reducing the relapse rate in patients with Crohn's disease, and in ameliorating the rate of abortion in women with recurrent spontaneous abortions; evidence is accumulating that the immunosuppression associated to perioperative ABT might adversely affect overall prognosis in patients with a malignancy undergoing curative cancer surgery. In addition, the ABT-associated immunomodulation has been reported to be associated with an increased risk for postoperative bacterial infections. Data from both inbred and outbred experimental animal models indicate that ABT promote tumor growth. Evidence is available that this ABT-promoting tumor growth effect can be adoptively transferred to naive animals, using splenic immunocytes. Furthermore, data from the experimental animal models indicate that the ABT effect on the growth of tumors is due to the presence of the donor leukocytes in the transfused allogeneic blood, and that this deleterious effect can be ameliorated by the pre-storage leukodepletion of the allogeneic blood. Importantly, recent evidence suggests that post-storage leukodepletion is inefficacious in preventing the ABT-associated tumor growth promotion effect. While results from studies in experimental animals cannot necessarily be extrapolated to the clinical situation, these studies suggest that ABT promote tumor growth and that pre-storage leukodepletion ameliorates this effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The tumor growth-promoting effect of allogeneic blood transfusions. 771 92

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

It is known that an important curative benefit of allogeneic bone marrow transplantation (BAMT) in the treatment of hematolymphoid malignancies is a graft-vs.-tumor (GVT) effect. GVT activity has been attributed to mature immune cells contained within the graft because T-cell depletion of bone marrow results in increased rates of disease relapse post-transplantation. We previously demonstrated successful engraftment of highly purified hematopoietic stem cells (HSCs) transplanted across major histocompatibility complex (MHC) barriers in mice. In the present study, we have developed a preclinical model of allogeneic HSC transplantation into lymphoma-inoculated mice, allowing us to directly test whether purified HSCs have measurable GVT activity. We then performed cotransfer studies of HSCs with purified immune cells to identify which population(s) confers tumor protection and the mechanism by which such cells suppress tumor growth. MHC-mismatched donor-recipient combinations were studied. All of the GVT activity was contained in the CD8+ cell fraction and, at the doses of CD8+ cells tested, tumor protection was separable from acute graft-vs.-host disease (aGVHD). Although there appears to be no functional difference between BM- and splenic-derived CDS8+ cells with regard to GVT activity without aGVHD, this was not the case for purified CD3+ cells. CD3+ cells derived from BM were tumor protective, whereas transplantation of equivalent doses of CD3+ cells purified from spleen resulted in lethal GVHD. The mechanism by which the GVT-conferring cells protect recipient mice from tumors was studied using immune defective mice as donors. We found that an intact pathway of perforin-dependent cytolysis, as well as an intact Fas-ligand pathway, is required in order to exert maximal anti-tumor activity.
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PMID:Graft-vs.-lymphoma effect in an allogeneic hematopoietic stem cell transplantation model. 1059 13

Allogeneic bone marrow transplantation (BMT) induces 2 closely associated immune responses: graft-versus-tumor (GVT) activity and graft-versus-host disease (GVHD). We have previously shown that pretransplant immunization of allogeneic BMT donors with a recipient-derived tumor cell vaccine increases both GVT activity and lethal GVHD because of the priming of donor T cells against putative minor histocompatibility antigens (mHAgs) on the tumor vaccine cells. The work reported here tested the hypothesis that tumor cell vaccination after BMT would produce an increase in GVT activity without exacerbating GVHD. C3H.SW donor bone marrow and splenocytes were transplanted into major histocompatibility complex-matched, mHAg-mismatched C57BL/6 recipients. One month after BMT, recipients were immunized against either a C57BL/6 myeloid leukemia (C1498) or fibrosarcoma (205). Immunized recipients had a significant increase in survival and protection against tumor growth in both tumor models, and significant tumor protection was seen even in recipients with preexisting micrometastatic cancer before immunization. Alloreactivity appeared to contribute to the in vitro anti-tumor cytolytic activity, but in vivo immunity was tumor specific, and no exacerbation of GVHD was observed. Although the immunodominant mHAg B6(dom1) was shown to be expressed by all B6 tumors tested and was largely responsible for the alloreactivity resulting from tumor immunization of donors, the in vitro alloreactivity of immune recipients was more restricted and was not mediated by recognition of B6(dom1). In conclusion, post-transplant tumor immunization of allogeneic BMT recipients against either a leukemia or a solid tumor can increase GVT activity and survival without exacerbating GVHD.
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PMID:Immunization of allogeneic bone marrow transplant recipients with tumor cell vaccines enhances graft-versus-tumor activity without exacerbating graft-versus-host disease. 1073 17

Allogeneic bone marrow transplantation (BMT) causes a beneficial graft-versus-tumor (GVT) immune response that is often associated with graft-versus-host disease (GVHD). There is substantial interest in developing therapeutic strategies that augment GVT without GVHD. We have demonstrated recently that immunization of BMT donors with cellular tumor vaccines leads to curative GVT but induces unacceptable GVHD because of the presence of recipient minor histocompatibility antigens (mHAgs) in whole-cell tumor vaccines. This study tested the hypothesis that immunization of BMT donors against a defined tumor-specific antigen with a vaccine not containing recipient mHAgs would help to separate the two responses by enhancing GVT activity without exacerbating GVHD, even when cellular vaccines were used after BMT. Recipient strain C57BL/6 fibrosarcoma cells engineered to express the well-characterized model tumor antigen, influenza nucleoprotein (NP), were used in these studies. C3H.SW donors were immunized against NP prior to BMT, and cytolytic T cells were transferred along with bone marrow into irradiated H-2-matched, mHAg-mismatched C57BL/6 recipients with established micrometastatic 205-NP tumors. Donor immunization led to a significant increase in GVT activity, as measured by reduction in tumor growth and enhanced survival. However, deaths in recipients of tumor antigen-specific immune BMT ultimately occurred because of the growth of antigen-loss variants; such tumor growth did not occur in animals receiving BMT from donors treated with whole-cell vaccines. Donor immunization did not lead to an exacerbation of GVHD, even when BMT recipients received additional immunization after BMT with a 205-NP "whole" tumor cell vaccine (which was shown to induce fatal GVHD when used for donor immunization). In conclusion, immunization of allogeneic BMT donors against a tumor-specific antigen significantly enhances GVT activity without an associated exacerbation of GVHD.
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PMID:Pretransplant tumor antigen-specific immunization of allogeneic bone marrow transplant donors enhances graft-versus-tumor activity without exacerbation of graft-versus-host disease. 1105 76

Cell therapy with allogeneic donor cells mismatched for minor histocompatible (MiHC) antigens was applied to a murine mammary carcinoma (4T1) model to test the feasibility of graft versus tumor (GVT) effect against metastatic epithelial tumor cells. BALB/c mice bearing a 4T1 tumor of BALB/c origin were given syngeneic or MiHC-mismatched splenocytes. GVT effects were determined in secondary recipients of adoptively transferred lung cells derived from primary hosts who had previously been inoculated intravenously with 4T1 cells, and injected with one of the following: 1) naive BALB/c splenocytes, 2) naive DBA/2 splenocytes, 3) 4T1-immune DBA/2 splenocytes, or 4) DBA/2 splenocytes immunized with host-derived BABL/c spleen cells. Naive DBA/2 splenocytes inhibited tumor growth only slightly and only slightly prolonged the survival of secondary recipients, in comparison with fully matched tumor/host BALB/c spleen cells. An efficient GVT reaction was demonstrated in vitro and in vivo with MiHC-mismatched DBA/2 splenocytes from mice presensitized by multiple injections of irradiated tumor or BALB/c-derived spleen cells. All 30 mice adoptively inoculated with lung cells from primary hosts that had previously been treated with these presensitized effector cells were tumor free for >250 days. Secondary recipients inoculated with lung cells from mice given naive BALB/c or DBA/2 spleen cells died of metastatic tumors within 33 to 46 days. These results suggest that preimmunized donor cells represent an effective tool against metastatic disease; hence, the next goal should be to control graft-versus-host disease while exploiting the GVT potential.
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PMID:Cell therapy with preimmunized effector cells mismatched for minor histocompatible antigens in the treatment of a murine mammary carcinoma. 1126 65

SUMMARY: Cell therapy with allogeneic donor cells mismatched for minor histocompatible (MiHC) antigens was applied to a murine mammary carcinoma (4T1) model to test the feasibility of graft versus tumor (GVT) effect against metastatic epithelial tumor cells. BALB/c mice bearing a 4T1 tumor of BALB/c origin were given syngeneic or MiHC-mismatched splenocytes. GVT effects were determined in secondary recipients of adoptively transferred lung cells derived from primary hosts who had previously been inoculated intravenously with 4T1 cells, and injected with one of the following: 1) naive BALB/c splenocytes, 2) naive DBA/2 splenocytes, 3) 4T1-immune DBA/2 splenocytes, or 4) DBA/2 splenocytes immunized with host-derived BABL/c spleen cells. Naive DBA/2 splenocytes inhibited tumor growth only slightly and only slightly prolonged the survival of secondary recipients, in comparison with fully matched tumor/host BALB/c spleen cells. An efficient GVT reaction was demonstrated in vitro and in vivo with MiHC-mismatched DBA/2 splenocytes from mice presensitized by multiple injections of irradiated tumor or BALB/c-derived spleen cells. All 30 mice adoptively inoculated with lung cells from primary hosts that had previously been treated with these presensitized effector cells were tumor free for >250 days. Secondary recipients inoculated with lung cells from mice given naive BALB/c or DBA/2 spleen cells died of metastatic tumors within 33 to 46 days. These results suggest that preimmunized donor cells represent an effective tool against metastatic disease; hence, the next goal should be to control graft-versus-host disease while exploiting the GVT potential.
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PMID:Cell Therapy With Preimmunized Effector Cells Mismatched for Minor Histocompatible Antigens in the Treatment of a Murine Mammary Carcinoma. 1144 67

Hematopoietic stem cell transplants (SCT) are used in the treatment of neoplastic diseases, in addition to congenital, autoimmune, and inflammatory disorders. Both autologous and allogeneic SCT are used, depending on donor availability and the type of disease being treated, resulting in different morbidity and outcomes. In both types of SCT, immune regulation via graft manipulation is being studied, although with highly different targeted outcomes. In general, autologous SCT have lower treatment-related morbidity and mortality, but a higher incidence of tumor relapse, and graft manipulation targets immune augmentation and/or the reduction of immune tolerance. In contrast, allogeneic SCT have a higher incidence of treatment-related morbidity and mortality and a significantly longer time of disease progression, and the targeted outcomes or graft manipulation focus on a reduction in graft versus host disease (GVHD). One source of the increased relapse rate and shorter overall survival (OS) following high dose chemotherapy (HDT) and autologous SCT is the immune tolerance that limits host response, both innate and antigen (Ag) specific, against the tumor. The immune tolerance that is observed is due in part to the tumor burden and prior cytotoxic therapy. Therefore, graft manipulation, as an adjuvant therapeutic approach in autologous SCT, is primarily focused on non-specific or specific immune augmentation using cytokines and vaccines. Recently, manipulation of the infused product as a form of cellular therapy has begun to also focus on approaches to reduce immune tolerance found in transplant patients, both prior to and following HDT and SCT. To this end, graft manipulation to reduce the presence of Fas Ligand (FasL)-expressing cells or interleukin (IL)10 and tumor growth factor (TGF)beta production has been proposed. In contrast to autologous transplantation, graft manipulation during allogeneic transplantation is used extensively. This includes limiting the infusion of T cells within the product or as a donor leukocyte infusion (DLI), resulting in a reduction in GVHD and the induction of long-term survivors. Indeed, allogeneic SCT provide the only curative therapy for patients with chronic myelogenous leukemia (CML), refractory acute leukemia, and myelodysplasia. The curative potential of allogeneic SCT is reduced, however, by the development of GVHD, a potentially lethal T-cell-mediated immune response targeting host tissues [Int. Arch. Allergy Immunol. 102 (1993) 309, J. Exp. Med. 183 (1996) 589]. The morbidity and mortality associated with GVHD limit this technology, resulting focus on those patients who have no alternative therapeutic options or who have advanced disease. Thus, allogeneic SCT provide one of the few statistically supported demonstrations of therapeutic efficacy by T cells (comparison of allogeneic to autologous transplantation). In contrast to autologous transplantation, control of GVHD following allogeneic SCT focuses on immune suppression and the induction of tolerance. Here too, graft manipulation is appropriate, and there are numerous studies of T-cell depletion to reduce GVHD, with or without the isolation and infusion of T cells as DLI. Additional strategies are examining the isolation and infusion of T cells with graft versus leukemia (GVL) activity to reduce GVHD and/or the infusion of genetically manipulated and/or selected cellular populations (monocytes or dendritic cells (DC)) to induce tolerance. Therefore, depending upon the type of transplant, the goals associated with graft manipulation can be radically different. In this review, we emphasize using graft manipulation to regulate immune tolerance and anergy in association with SCT. Although this paper focuses on hematopoietic SCT, it should be noted that these strategies are relevant to conditions other than neoplastic and congenital diseases, including solid organ transplants, and autoimmune and inflammatory diseases.
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PMID:Hematopoietic stem cell graft manipulation as a mechanism of immunotherapy. 1286 Jan 68


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