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Margot Zöller

Publications and source records attributed to Margot Zöller.

At least 37 records · Page 2Linked to original sources
PubMed2004

Characterization of tumor reactivity of human V gamma 9V delta 2 gamma delta T cells in vitro and in SCID mice in vivo.

Human Vgamma9Vdelta2 gammadelta T cells are selectively activated by bacterial phosphoantigens and aminobisphosphonates and exert potent cytotoxicity toward various tumor cells. In this study we have characterized the cytotoxic reactivity of gammadelta T cell lines established from healthy donors by stimulation with aminobisphosphonate alendronate toward melanoma MeWo and pancreatic adenocarcinomas Colo357 and PancTu1 lines in vitro and in vivo upon adoptive transfer into SCID mice. Lysis of all tumor cells was enhanced when gammadelta effector cells were preactivated with phosphoantigens. Recognition of MeWo was TCR dependent, as shown by anti-TCR Ab blockade, whereas only the phosphoantigen-mediated increased, but not the basal, lysis of Colo357 and PancTu1 was inhibited by anti-TCR Ab. Furthermore, lysis of Colo357, but not that of MeWo or PancTu1, was completely inhibited by the pan-caspase inhibitor zVAD, indicating different recognition and effector mechanisms involved in the gammadelta T cell/tumor cell interactions. Upon transfer into SCID mice, alendronate-activated gammadelta T cells given together with IL-2 and alendronate significantly prolonged the survival of SCID mice inoculated with human tumor cells. The best results were thus obtained when gammadelta T cells were repetitively given five times over a period of 30 days. With this protocol, human gammadelta T cells prolonged the mean survival of mice inoculated with MeWo melanoma from 28.5 to 87.3 days (p < 0.0001) and in the case of PancTu1 adenocarcinoma from 23.0 to 48.4 days (p < 0.0001). We conclude that an effective gammadelta T cell-based immunotherapy might require activation of endogenous gammadelta T cells with aminobisphosphonate (or phosphoantigen) and IL-2, followed by adoptive transfer of in vitro expanded gammadelta T cells.

Adenocarcinoma↗
PubMed2004

CD44 variant isoforms associate with tetraspanins and EpCAM.

The metastasizing subline of the rat pancreatic adenocarcinoma BSp73 expresses a set of membrane molecules, the combination of which has not been detected on non-metastasizing tumor lines. Hence, it became of interest whether these molecules function independently or may associate and exert specialized functions as membrane complexes. Separation of CD44v4-v7 containing membrane complexes in mild detergent revealed an association with the alpha3 integrin, annexin I, EpCAM, and the tetraspanins D6.1A and CD9. EpCAM and the tetraspanins associate selectively with CD44 variant (CD44v), but not with the CD44 standard (CD44s) isoform. The complexes are found in glycolipid-enriched membrane (GEM) microdomains, which are dissolved by stringent detergents, but the complexes are not destroyed by methyl-beta-cyclodextrin (MbetaCD) treatment, which implies that complex formation does not depend on a lipid-rich microenvironment. However, a complex-associated impact on cell-matrix and cell-cell adhesion as well as on resistance towards apoptosis essentially depended on the location in GEMs. Thus, CD44v-specific functions may well be brought about by complex formation of CD44v with EpCAM, the tetraspanins, and the alpha3 integrin. Because CD44v4-v7-EpCAM complex-specific functions strictly depended on the GEM localization, linker or signal-transducing molecules associating with the complex are likely located in GEMs.

Adenocarcinoma↗
PubMed2004

Synthesis and structure-activity relationship of novel antitumoral platinum xanthate complexes.

To establish structure-activity relationships, derivatives of a recently described sulfur-containing antitumoral platinum complex, bis(O-ethyldithiocarbonato)platinum(II), named thioplatin, were analyzed. Twenty different bis(O-alkyldithiocarbonato)platinum(II) complexes were synthesized and tested for cytotoxic activity in a panel of six human tumor lines. Derivatives with up to 7-fold increased activity compared to thioplatin and up to 25-fold more activity than cisplatin were identified. Bis(O-alkyldithiocarbonato)platinum(II) complexes with short n-alkyl chains such as methyl, ethyl, propyl, and butyl were found to be superior to compounds with long n-alkyl chains such as hexyl, octyl, and decyl. Complexes derived from secondary xanthates displayed significantly higher activity than those derived from primary xanthates with the same number of C atoms. Like thioplatin, all tested platinum complexes were more active at pH 6.8 than at pH 7.4. A pH of 6.8 and lower has been frequently found in solid tumors because of the tendency of tumor cells to undergo anaerobic fermentation. Drugs with such pH-dependent antitumoral activity have an improved therapeutic index compared to drugs that are active irrespective of pH.

Antineoplastic Agents↗
PubMed2004

Immunotherapy of cancer for the elderly patient: does allogeneic bone marrow transplantation after nonmyeloablative conditioning provide a new option?

The critical role of antigen-specific T cells in cancer immunotherapy has been amply demonstrated. Though success of clinical trials still remains far behind expectations, the continuous improvement in our understanding of the biology of the immune response will provide the basis for optimized cancer vaccines. This review focuses on active therapeutic vaccination after allogeneic bone marrow cell transplantation with nonmyeloablative conditioning. This approach could provide a major breakthrough in cancer immunotherapy, particularly of elderly patients. The senescent immune system, mainly the T-cell compartment, displays reduced responsiveness, and this has to be overcome if therapeutic vaccination is to be of benefit for the patient. Although the defects are quite well characterized, the inducing factors and ways to overcome them are still to be explored in more detail. Many questions also remain to be answered in the field of allogeneic bone marrow transplantation after nonmyeloablative conditioning to optimize this therapeutic setting in cancer immunotherapy. Current considerations to improve engraftment and to reduce graft-versus-host disease while strengthening graft-versus-tumor reactivity will be briefly reviewed. Finally, I will discuss whether tumor-reactive T cells can be "naturally" maintained during the process of T-cell maturation in the allogeneic host. Provided this hypothesis can be substantiated, a T-cell vaccine will meet a pool of virgin T cells in the allogeneically reconstituted host, which are tolerant toward the host but not anergized toward tumor antigens presented by MHC molecules of the host. Inevitably, the problem of the aged immune system would be circumvented.

Aged↗
PubMed2004

Apoptosis resistance in peripheral blood lymphocytes of alopecia areata patients.

Alopecia areata (AA) is a putative, cell-mediated autoimmune disease of anagen stage hair follicles. Inter- and intra-follicular lymphocytic infiltrates are associated with alopecia that may progress from an initially patchy presentation to extensive, even universal, hair loss. We previously noted in a mouse model of AA that regulatory T cells (Treg) are absent from draining lymph nodes and that expression of CD44v7 is transiently upregulated. Both features might explain autoreactive T cell persistence. Here we explored whether similar changes are seen in AA patients' peripheral blood mononuclear cells (PBMC). There was no clear evidence for a reduction in Treg as a possible means to support sustained T cell activation. However, progressive AA patients' PBMC displayed increased resistance towards apoptosis, which was accompanied by a decrease in CD95L+ and an increase in CD44v7+ cells. Notably, an expanded population of CD4+CD25+CD154+ T cells in progressive AA patients' PBMC was apoptosis resistant and expressed CD44v7. Thus, survival of activated T cells in progressive AA patients' PBMC is apparently sustained by downregulation of CD95L and upregulation of CD44v7 which is known to be associated with anti-apoptotic gene expression.

Adolescent↗
PubMed2004

The progressive state, in contrast to the stable or regressive state of alopecia areata, is reflected in peripheral blood mononuclear cells.

Alopecia areata (AA) is a putative autoimmune disease of the skin with an inflammatory component that can be treated by the local application of contact sensitizers. Here, we explored whether responsiveness toward diphenylcyclopropenone (DPCP) is reflected by the composition and the activation state of peripheral blood mononuclear cells (PBMCs). PBMCs of 43 AA patients, 26 treated and 17 untreated, and of 31 healthy volunteers were tested. AA patients' PBMCs differed from that of healthy donors by a slight increase in CD16- and tumor necrosis factor-alpha (TNF-alpha)-expressing cells. These features were independent of the disease state and treatment. Additional changes in the activation state of PBMCs, upregulation of the costimulatory molecules CD40 and CD80, of the accessory molecule CD154, and of interferon-gamma expression were identified only in AA patients where the disease was advancing, i.e. these changes were independent of the extent of hair loss and were not seen in patients with spontaneous or DPCP treatment-induced, regressing AA. Thus, the progressive state of AA is accompanied by a systemic activation of T cells, and the therapeutic efficacy of treatment can be estimated by restoration of the non-activated state. Furthermore, an increase in CD16(+)- and TNF-alpha-expressing cells may contribute to AA susceptibility.

Adolescent↗
PubMed2003

Tumor vaccination after allogeneic bone marrow cell reconstitution of the nonmyeloablatively conditioned tumor-bearing murine host.

Allogeneic bone marrow cell reconstitution of the nonmyeloablatively conditioned host is supposed to provide an optimized platform for tumor vaccination. We recently showed that an allogeneic T cell-depleted graft was well accepted if the tumor-bearing host was NK depleted. Based on this finding, a vaccination protocol in tumor-bearing, nonmyeloablatively conditioned, allogeneically reconstituted mice was elaborated. Allogeneically reconstituted mice, bearing a renal cell carcinoma, received tumor-primed donor lymph node cells (LNC), which had or had not matured in the allogeneic host. Primed LNC were supported by tumor lysate-pulsed dendritic cells, which were donor or host derived. Optimal responses against the tumor were observed with host-tolerant, tumor-primed LNC in combination with host-derived dendritic cells. High frequencies of tumor-specific proliferating and CTLs were recorded; the survival time of tumor-bearing mice was significantly prolonged, and in >50% of mice the tumor was completely rejected. Notably, severe graft-vs-host disease was observed in reconstituted mice that received tumor-primed LNC, which had not matured in the allogeneic host. However, graft-vs-host was not aggravated after vaccination with tumor-primed, host-tolerant LNC. Thus, the LNC were tolerant toward the host, but not toward the tumor. The finding convincingly demonstrates the feasibility and efficacy of tumor vaccination after allogeneic reconstitution of the nonmyeloablatively conditioned host.

Animals↗
PubMed2003

The association of the tetraspanin D6.1A with the alpha6beta4 integrin supports cell motility and liver metastasis formation.

The metastatic subline of a rat pancreatic adenocarcinoma differs from the non-metastasizing subline by overexpression of 5 membrane molecules: CD44 variant isoforms, EpCAM, the tetraspanin D6.1A, an uPAR-related molecule and, as described here, the alpha6beta4 integrin. An antibody-defined molecule was identified by mass spectrometry and cloning as alpha6beta4 integrin. Transfection-induced expression of alpha6beta4 in the non-metastasizing subline did not support migration on laminin 5 or tumor progression. However, when the non-metastasizing subline was doubly transfected to express alpha6beta4 and the D6.1A tetraspanin, intraperitoneally injected tumor cells frequently formed liver metastasis. For the following reasons we assume that metastasis formation is supported by an interaction between alpha6beta4 and D6.1A. (i) The 2 molecules can associate and co-localize. (ii) Co-localization is strengthened by PKC stimulation. (iii) PKC stimulation, which induces a migratory phenotype, leads to a redistribution of alpha6beta4/D6.1A complexes. In resting cells, the molecules co-localize at the trail of the cell; during PKC stimulation they become transiently internalized and are (re-)expressed in the leading lamella. Thus, in the appropriate milieu, i.e. intraperitoneally, alpha6beta4 changes from an adhesion-supporting towards a migration-supporting molecule by its association with a tetraspanin. The findings provide a convincing experimental explanation for the repeatedly described involvement of alpha6beta4 in tumor progression.

Amino Acid Sequence↗
PubMed2003

Alopecia areata susceptibility in rodent models.

With our current view of alopecia areata as an autoimmune disease, it is probable that disease development in an individual is dependent on multiple genetic and environmental factors interacting in a complex system. Rodent models afford the opportunity to investigate alopecia areata development and to define the significance of the different factors involved. Recently, rodent model characterization has been conducted using flow cytometry, microarray analysis, and functional studies. From these a pattern of events in alopecia areata development has emerged. Although the preliminary activation events for the onset of alopecia areata remain unknown, the response of the immune system is characterized by antigen presentation and costimulation of lymphocytes in the lymph nodes and skin, a deficiency of CD4+/CD25+ regulatory cells, and an action of activated lymphocytes on hair follicles via Fas/FasL signaling and cytokines. Thus, onset of disease may require appropriate (or inappropriate) expression of stimulatory antigens within the hair follicle, the breakdown of the putative hair follicle immune privilege, the presentation of antigens to the immune system, a failure of immune system regulation, and the ability of the activated immune system to disrupt anagen-stage hair follicles. Once the sequence of events is initiated, it may become a self-perpetuating cycle, with epitope spreading leading to a wider range of targets in chronic alopecia areata. Rodent model studies have provided significant insight into alopecia areata, but much more remains to be explained about the mechanisms of disease development.

Alopecia Areata↗
PubMed2003

Immunotherapy of cancer by active vaccination: does allogeneic bone marrow transplantation after non-myeloablative conditioning provide a new option?

The critical role of antigen-specific T cells in cancer immunotherapy has been amply demonstrated in many model systems. Though success of clinical trials still remains far behind expectation, the continuous improvement in our understanding of the biology of the immune response will provide the basis of optimized cancer vaccines and allow for new modalities of cancer treatment. This review focuses on the current status of active therapeutic vaccination and future prospects. The latter will mainly be concerned with allogeneic bone marrow cell transplantation after non-myeloablative conditioning, because it is my belief that this approach could provide a major breakthrough in cancer immunotherapy. Concerning active vaccination protocols the following aspects will be addressed: i) the targets of immunotherapeutic approaches; ii) the response elements needed for raising a therapeutically successful immune reaction; iii) ways to achieve an optimal confrontation of the immune system with the tumor and iv) supportive regimen of immunomodulation. Hazards which one is most frequently confronted with in trials to attack tumors with the inherent weapon of immune defense will only be briefly mentioned. Many question remain to be answered in the field of allogeneic bone marrow transplantation after non-myeloablative conditioning to optimize the therapeutic setting for this likely very powerful tool of cancer therapy. Current considerations to improve engraftment and to reduce graft versus host disease while strengthening graft versus tumor reactivity will be briefly reviewed. Finally, I will discuss whether tumor-reactive T cells can be "naturally" maintained during the process of T cell maturation in the allogeneic host. Provided this hypothesis can be substantiated, a T cell vaccine will meet a pool of virgin T cells in the allogeneically reconstituted host, which are tolerant towards the host, but not anergised towards tumor antigens presented by MHC molecules of the host.

Animals↗
PubMed2003

CD44v7 interferes with activation-induced cell death by up-regulation of anti-apoptotic gene expression.

Blockade of CD44v7 was described to cure trinitrobenzene sulfonic acid-induced colitis, a disease not developed by mice with targeted deletion of the CD44v7 exon. There was evidence for a reduction in activation-induced cell death on lamina propria lymphocytes of control as compared with CD44v7-deficient mice. To elucidate the mechanism underlying the relative apoptosis resistance of CD44v7-competent as compared with CD44v7-deficient lymphocytes, T cell activation and induction of apoptosis were analyzed on mesenteric lymph node cells and Peyer's patch lymphocytes of CD44v7-deficient and CD44v4-v7-transgenic mice, which overexpress rat CD44v4-v7 on T lymphocytes. CD44v7 deficiency was characterized by an increase in the percentage of apoptotic cells after stimulation, increased numbers of CD95L- and CD152-positive cells, low levels of the anti-apoptotic proteins Bcl-2 and Bcl-Xl, and decreased phosphorylation of the pro-apoptotic protein BAD. Also, lymphocytes from CD44v4-v7-transgenic mice displayed reduced levels of CD95L, low numbers of apoptotic cells, and constitutively elevated levels of Bcl-Xl. When stimulating lymphocytes by CD3 cross-linking, CD44v7 was not recruited toward the immunological synapse and preferentially associated with the cytoskeletal-linker protein ezrin. Thus, as opposed to the CD44 standard isoform, CD44v7 does not function as an accessory molecule; instead, it supports survival of activated T cells by interfering with activation-induced cell death.

Animals↗
PubMed2002

Transient CD44 variant isoform expression and reduction in CD4(+)/CD25(+) regulatory T cells in C3H/HeJ mice with alopecia areata.

Alopecia areata, an autoimmune disease affecting anagen stage hair follicles, can be induced by grafting spontaneous alopecia areata affected skin to normal-haired C3H/HeJ mice. As the onset of alopecia areata can be significantly retarded by anti-CD44 variant isoform 10 treatment, it was interesting to explore the underlying disease mechanism. Two weeks after transplanting alopecia areata affected skin, expression of CD44 variant isoforms 3, 6, 7, and 10 was strikingly upregulated as compared with sham-grafted mice. By 6 wk after grafting, CD44 variant isoform levels had returned to normal, whereas in draining lymph nodes, CD44 variant isoform expression was slightly decreased. Leukocytes in the skin of mice with chronic alopecia areata expressed a hematopoietic isoform of CD44 and CD44 variant isoform 6 at an elevated level, but CD44 variant isoform 3 expression was reduced. Cytokine expression in leukocytes of chronic alopecia areata affected skin was higher than in normal-haired controls. Cytokine expression also increased postsurgery in sham and alopecia areata grafted mice, but remained elevated only in mice receiving alopecia areata affected skin. Finally, from the skin of mice with chronic alopecia areata and of mice transplanted with alopecia areata affected skin, an increased number of CD4(+) and CD8(+) cells, but a strongly decreased number of CD4(+)/CD25(+) regulatory T cells was recovered. Thus, expression of CD44 variant isoforms is important for the migration of leukocytes during the initial period of alopecia areata. CD44, however, is apparently not involved in the maintenance of the disease state, which is characterized by high cytokine expression levels, an increased number of CD4(+) and CD8+ cells, but a low level of CD4(+)/CD25(+) suppressor cells.

Alopecia Areata↗
PubMed2002

Resistance to alopecia areata in C3H/HeJ mice is associated with increased expression of regulatory cytokines and a failure to recruit CD4+ and CD8+ cells.

Grafting alopecia areata affected C3H/HeJ mouse skin to littermates induces alopecia areata, but high dietary soy oil reduces alopecia areata susceptibility. Alopecia areata affected and resistant mice were characterized to evaluate possible mechanisms involved in alopecia areata resistance. Of 44 mice that received alopecia areata affected skin grafts but failed to develop alopecia areata, only two of 22 receiving further alopecia areata affected skin grafts developed alopecia areata, whereas 39 of 44 controls developed alopecia areata. Alopecia areata affected skin contained increased numbers of CD4+ and CD8+ cells, increases in pro inflammatory T helper 1 and T helper 2 type cytokines, and upregulation of CD28, CD40L, and their ligands. In draining lymph nodes, a relatively high number of antigen-presenting cells was recovered, whereas several CD44v variants were downregulated. In contrast, alopecia areata resistant mouse skin did not display increased numbers of CD4+ and CD8+ cells, whereas counter-regulatory cytokines interleukins 4 and 10 were upregulated. High expression of CD28, CD80, CD86, CD40, CTLA4, CD44v variants, and FasL occurred in alopecia areata resistant mouse spleens. In vitro, lymph node cells of susceptible and resistant mice responded equally to a mitogenic stimulus, but only lymph node cells from alopecia areata affected mice displayed an increased response with T cell receptor stimulation via anti-CD3 cross-linking. These results suggest alopecia areata is a cell-mediated autoimmune disease, but alopecia areata affected skin graft hosts may resist alopecia areata onset through active counter-regulatory mechanisms. Because alopecia areata resistant mice showed unimpaired responsiveness and a transient inflammatory response towards the graft, it is suggested that alopecia areata develops as a consequence of an inappropriate immune response regulation.

Alopecia Areata↗
PubMed2002

Allogeneic reconstitution after nonmyeloablative conditioning: mitigation of graft-versus-host and host-versus-graft reactivity by anti-CD44v6.

T-cell maturation is accelerated in transgenic mice expressing rat CD44v4-v7 on T cells, the effect being blocked by anti-CD44v6. This finding suggested functional activity of CD44v6 in thymocyte development. We tested the hypothesis by antibody blocking and using mice with targeted deletion of CD44v6/v7 exon products (CD44v6/v7(-/-)). When lethally irradiated CD44v6/v7-competent (CD44v6/v7(+/+)) mice were reconstituted syngeneically, higher numbers of CD44v6/v7(-/-) than CD44v6/v7(+/+) BMC were required for survival, the period of reconstitution was prolonged, and regain of immunocompetence was delayed. Similar findings were observed in lethally irradiated, anti-CD44v6-treated syngeneic CD44v6/v7(+/+) hosts. Thus, CD44v6/v7 supports maturation and expansion of hematopoietic progenitor cells. Surprisingly, reconstitution with CD44v6/v7(-/-) BMC or anti-CD44v6 treatment of the nonlethally irradiated allogeneic CD44v6/v7(+/+) host had only a minor impact on survival rates. When nonlethally irradiated CD44v6/v7(-/-) hosts received an allogeneic graft, survival rates were improved. These phenomena have been a result of reduced GvH reactivities when the donor was CD44v6/v7(-/-) and reduced HvG reactivities in the CD44v6/v7(-/-) host. Thus, although a deficit or blockade of CD44v6/v7 has a negative impact on hematopoietic reconstitution, a transient blockade will be of benefit for the allogeneically reconstituted host because of a strong reduction in GvH and HvG reactivities.

Animals↗
PubMed2002

Active vaccination after allogeneic bone marrow cell transplantation: a new option in the immunotherapy of cancer?

The concept of immunotherapy of cancer was evoked more than a century ago by W. Coley. Yet it is only recently that the state of knowledge allows for molecularly defined therapeutic approaches and much effort will still be required to place immunotherapy beside of surgery, chemotherapy and radiation as a fourth option. In this review, we will focus chiefly on two aspects: active therapeutic vaccination, because it is our belief that this approach will provide a major breakthrough, and the potential efficacy of combining active vaccination with allogeneic bone marrow cell transplantation. It was recently established in clinical trials that allogeneic bone marrow cell transplantation does not require myeloablative conditioning. Non-myeloabaltive conditioning, which avoids the high toxicity of the conventional approach, it is only kind which allows the recruitment of elderly patients and patients in poor health. Concerning active vaccination protocols, we will address the questions 1) what the targets (i.e. the antigens) of immunotherapeutic approaches could be; 2) how to achieve an optimal confrontation of the immune system with these tumor-associated antigens; and 3) which response elements are needed for raising a therapeutically successful immune reaction against these antigens. Many question remain to be answered in the field of allogeneic bone marrow transplantation after non-myelablative conditioning to optimize the therapeutic setting for this, most likely, very powerful tool of cancer therapy. We will briefly summarize current considerations to improve engraftment, and reduce graft-versus-host disease while strengthening graft-versus-tumor reactivity. There is some hope that the latter can be "naturally" maintained during the process of T cell maturation in the allogeneic host. Provided this hypothesis can be substantiated, the efficacy of active vaccination of the allogeneically reconstituted host will provide a pool of virgin T cells which are tolerant towards the host, but not anergized towards tumor antigens presented by MHC molecules of the host. We will only briefly mention supportive regimen of immunomodulation and those hazards which one is most frequently confronted with in attempts to attack tumors with the inherent weapon of immune defense. Though the successful immunotherapy of cancer still remains far behind expectations, there is a solid basis for the belief that, by improving our understanding of the molecular mechanisms of immunity, this may become a very powerful and less harmful tool than conventional therapies.

Antibodies, Monoclonal↗
PubMed2002

Donor T cell and host NK depletion improve the therapeutic efficacy of allogeneic bone marrow cell reconstitution in the nonmyeloablatively conditioned tumor-bearing host.

Allogeneic bone marrow cell reconstitution of the nonmyeloablatively conditioned host has the advantage that it can be tolerated in suboptimal health conditions. However, the problem of graft versus host disease (GvHD) remains. Also, graft acceptance may become delicate, and HvGD may arise. We report here on advantages/disadvantages of host natural killer (NK) depletion and graft T cell depletion in fully allogeneic, healthy and solid tumor-bearing mice. NK depletion of the "healthy" host improved the survival rate, whereas graft T cell depletion was disadvantageous. In the tumor-bearing host, graft T cell depletion was beneficial when the host was NK-depleted. Host NK depletion facilitated B lymphopoiesis, repopulation of the thymus, expansion of donor cells, and tolerance induction. The disadvantage of graft T cell depletion in the "healthy" host was a result of delayed engraftment. Because in tumor-bearing mice, host but not graft hematopoiesis was strongly impaired, donor hematopoiesis dominated. Graft T cell depletion reduced GvHD but hardly interfered with engraftment. Importantly, graft-mediated tumor reactivity appeared late and was unimpaired when the graft was T cell-depleted. Thus, concomitant depletion of host NK and donor T cells is advantageous when approaching therapeutic treatment of solid tumors by allogeneic reconstitution of the nonmyeloablatively conditioned host.

Animals↗
PubMedDate not supplied

Unexpected induction of unresponsiveness by vaccination with transformed Salmonella typhimurium.

Rats vaccinated with attenuated Salmonella typhimurium transformed with a vector containing the v2 exon of CD44 (SL-v2) were not protected and developed thymic metastases at a high rate. This was surprising because there was evidence for concomitant induction of a CD44v2-specific helper and cytotoxic T-cell response. The inefficacy of vaccination was partly caused by tumor escape and tumor-induced immunosuppression. More important were the facts that (i) BSpl2v2 cells migrated from the intraperitoneal implantation site to the thymus and (ii) after vaccination with transformed attenuated Salmonella typhimurium, a small number of dendritic cells, which had transcribed the cDNA insert, were detected in the thymus. In the thymic environment, these v2 presenting dendritic cells, as well as the BSp12v2 tumor cells, supported tolerance induction. Thus, vaccination with tumor-associated differentiation antigens, which in many instances have induced antitumor response, may deteriorate survival time and rate if vaccination is accompanied by presentation of the antigen during intrathymic T-cell selection.

Amino Acid Sequence↗