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PubMed1988

Split tolerance induced by the intrathymic adoptive transfer of thymocyte stem cells.

The intrathymic transfer of semiallogeneic CD4/CD8 double-negative (DN) thymocyte stem cells into irradiated host mice resulted in a transient state of chimerism in adoptive host thymus, spleen, and lymph nodes. Host-derived T cells, isolated from the thymus and periphery of the chimeric mice, were found to be specifically nonresponsive to the MHC antigens of the semiallogeneic DN donor in cytotoxicity assays. This nonresponsiveness was not permanent, but persisted as long as appreciable numbers of Thy-1 alloantigen-positive progeny of the DN donor cells could be detected in the spleen and lymph nodes of adoptive host mice. FACS sorting of DN donor cells before intrathymic transfer indicated that nonresponsiveness could be induced by Thy-1+ cells and was therefore not attributable to contaminating thymic macrophages, dendritic cells, or B cells. When FACS-sorted Thy-1+ (bm5 x bm12)F1 DN cells were transferred intrathymically into C57BL/6 hosts, nonresponsiveness to DN donor MHC class I but not class II alloantigen (split tolerance) was observed. These experiments were repeated using FACS-sorted Thy-1+ DN donor cells that were semiallogeneic to the irradiated adoptive host at either MHC class I or class II locus with similar results. Limiting dilution analysis showed that host-derived CTL precursors were tolerant of DN donor MHC class I alloantigen and no evidence for the involvement of suppressor T cells was found. The data indicate that murine thymocytes themselves are capable of tolerizing to MHC class I but not class II alloantigen after intrathymic transfer. The implications for intrathymic T cell differentiation and maintenance of self tolerance are discussed.

Animals↗
PubMed2003

Clinical course and immune response of a renal cell carcinoma patient to adoptive transfer of autologous cytotoxic T lymphocytes.

The cytotoxic T lymphocyte (CTL) is a promising candidate for an effector cell in adoptive immunotherapy for renal cell carcinoma (RCC). Here we report the clinical course and in vivo immune responses of a RCC patient with bulky retroperitoneal lymph node (RPLN) metastases who received adoptive autologous CTL therapy. A 56-year-old woman diagnosed with RCC with multiple RPLN metastases underwent unilateral nephrectomy. Autologous RCC cells were primary-cultured from surgical specimens. Before addition of peripheral blood mononuclear cells (PBMC) for CTL induction, subconfluent RCC cells were irradiated with 50 Gy. The PBMCs were then cultured on RCC cells in the induction medium supplemented with four kinds of interleukins. The induced CTLs showed the potent killing activity against autologous RCC cells in a typical MHC-class I-restricted manner. The patient received three courses of CTL therapy with a total of 10.2 x 10(9) cells, and the RPLN mass decreased markedly in size after the second course. Eosinophilia and enhanced CTL inducibility from peripheral blood were observed after CTL administrations. The patient was progression free without further treatment; however, she developed rapidly progressive glomerulonephritis more than 1 year after the last treatment. The patient died of newly developed metastases 27 months after the start of CTL therapy. At autopsy, viable RCC cells were found in multiple metastatic sites. However, only diffuse fibrous tissue was observed in the responding RPLN mass. Apparent histological divergence was observed between primary and metastatic sites.

Carcinoma, Renal Cell↗
PubMed1999

Bone marrow stromal cells as a vehicle for gene transfer.

Adoptive transfer of genetically modified somatic cells is playing an increasingly important role in the management of a wide spectrum of human diseases. Hematopoietic stem cells and lymphocytes have been used to transfer a variety of genes, however, they have limitations. In this study, the feasibility of retroviral gene transduction of bone marrow stromal cells, and the engraftment characteristics of these cells following infusion, was investigated in a murine transplantation model. Stromal cells derived from Balb/c mouse bone marrow were transduced with a replication-defective retrovirus containing the LacZ gene. Following three rounds of transduction, between 5 and 40% of the cells were positive for the LacZ gene. A total of 2 x 106 cells were infused into the same mouse strain. After the infusion, the LacZ gene was detected by PCR in the bone marrow, spleen, liver, kidney and lung; however, only the spleen and bone marrow samples were strongly positive. Quantitative PCR demonstrated that between 3 and 5% of spleen and bone marrow cells, and 1% of liver cells contained the LacZ gene at 3 weeks after infusion; <0.2% transduced cells were found in other organs. No difference was noted in engraftment between mice with or without irradiation before transplantation, suggesting that engraftment occurred without myeloablation. The infused transduced cells persisted for up to 24 weeks. Self-renewal of transplanted stromal cells was demonstrated in secondary transplant studies. Ease of culture and gene transduction and tissue specificity to hematopoietic organs (bone marrow, spleen, liver) is demonstrated, indicating that stromal cells may be an ideal vehicle for gene transfer.

Adoptive Transfer↗
PubMed2005

Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells.

T cell differentiation is a progressive process characterized by phenotypic and functional changes. By transferring tumor-specific CD8+ T cells into tumor-bearing mice at various stages of differentiation, we evaluated their efficacy for adoptive immunotherapy. We found that administration of naive and early effector T cells, in combination with active immunization and IL-2, resulted in the eradication of large, established tumors. Despite enhanced in vitro antitumor properties, more-differentiated effector T cells were less effective for in vivo tumor treatment. Several events may underlie this paradoxical phenomenon: (a) downregulation of lymphoid-homing and costimulatory molecules; (b) inability to produce IL-2 and access homeostatic cytokines; and (c) entry into a proapoptotic and replicative senescent state. While the progressive acquisition of terminal effector properties is characterized by pronounced in vitro tumor killing, in vivo T cell activation, proliferation, and survival are progressively impaired. These findings suggest that the current methodology for selecting T cells for transfer is inadequate and provide new criteria for the generation and the screening of optimal lymphocyte populations for adoptive immunotherapy.

Animals↗
PubMed2004

Induction of unresponsiveness limits tumor protection by adoptively transferred MDM2-specific cytotoxic T lymphocytes.

There is evidence showing that high avidity CTLs can be more effective than low avidity CTLs for adoptive tumor immunotherapy. Because many T cell-recognized tumor antigens are nonmutated self-proteins, tolerance mechanisms are likely to render high avidity T cells unresponsive or cause T cell elimination by clonal deletion. We recently used the allo-restricted strategy to circumvent immunologic tolerance to a ubiquitously expressed tumor-associated protein, MDM2, and raised high avidity CTLs in humans and in mice. In this study, we investigated whether high avidity MDM2-specific CTLs can mediate tumor protection without causing damage to normal tissues in mice. Although the CTLs prolonged survival of tumor-bearing mice without causing damage to normal tissues, tumor protection was incomplete. We show that tumor growth occurred despite the continued presence of MDM2-specific CTLs and the continued susceptibility of tumor cells to CTL killing. However, analysis of the CTLs revealed that they had been rendered unresponsive in vivo because they did not produce interferon gamma in response to antigen-specific stimulation. These experiments suggest that induction of unresponsiveness may be an important mechanism limiting the efficacy of adoptive CTL therapy.

Animals↗
PubMed1994

Adoptively transferred ex vivo activated memory T cells with cyclophosphamide: effective tumor-specific chemoimmunotherapy of advanced metastatic murine melanoma and carcinoma.

Autolymphocyte therapy (ALT) is adoptive cellular therapy of neoplastic disease based upon ex vivo activation of autologous peripheral blood mononuclear cells by either the supernatant derived from a previously prepared one-way mixed lymphocyte culture (MLC) or using low doses of the mitogenic monoclonal antibody anti-CD3 and a mixture of previously prepared autologous cytokines (T3CS). We have previously demonstrated that nonspecific ex vivo activation of splenocytes from murine tumor-bearing hosts (TBH) using an MLC supernatant or T3CS without the use of tumor antigen results in the expansion of the CD44+ (memory) T-cell subset. These memory T cells or autolymphocytes (ALT cells) mediate in vivo specificity when infused into murine TBH. To determine if cyclophosphamide (CY) could enhance the effectiveness of these ALT cells, C57BL/6J TBH with B16 melanoma or Lewis lung (3LL) carcinoma were treated with adoptive chemoimmunotherapy (ACIT) consisting of ALT cells and varying doses of CY. ALT cells were derived from the splenocytes of C57BL/6J TBH with B16 melanoma or 3LL carcinoma and activated ex vivo with T3CS. 3LL or B16 TBH received ALT cells derived from 3LL TBH splenocytes, B16 TBH splenocytes, CY alone, or ACIT with ALT cells and CY. Significantly greater antitumor activity as demonstrated by a decreased number of lung metastases (Day 21) and cure of primary and metastatic disease (Day 100) was seen in B16 or 3LL TBH that received ACIT using CY with B16-derived and 3LL-derived ALT cells, respectively, rather than ALT cells alone, CY alone, or ACIT with CY and reciprocal tumor-derived ALT cells. TBH cured by ACIT using CY and ALT cells derived from syngeneic TBH with the identical tumor displayed tumor-specific immunity as they were able to reject a lethal challenge of their previous B16 or 3LL tumor but not reciprocal tumors. TBH cured by ACIT using CY and ALT cells derived from splenocytes of syngeneic TBH with reciprocal tumors were able to reject lethal challenges of both tumors. These data demonstrate that effective ACIT using CY combined with ex vivo T3CS-activated CD44+ memory T cells from TBH conveys long-term tumor-specific immunity.

Animals↗
PubMed1992

Antigen-specific inhibition of the adoptive transfer of experimental autoimmune encephalomyelitis in Lewis rats.

The efficacy of antigen-specific immunoregulation as a treatment for the efferent limb of an autoimmune disease was tested in a rat model of adoptive experimental autoimmune encephalomyelitis (EAE). Lewis rats receiving 4-5 x 10(7) guinea pig (GP) myelin basic protein (MBP)-activated lymph node T cell blasts from GPMBP/CFA sensitized donors routinely show clinical signs of disease 5-6 days post transfer. Intravenous injection of GPMBP coupled to syngeneic splenocytes using the chemical cross-linker carbodiimide was effective in completely abrogating the expression of clinical EAE in rats that received MBP-specific T cells 2 days previously. Partial inhibition was also observed in rats injected as early as day 0 (the same day as MBP-specific T cell transfer) and as late as 1 day prior to the onset of clinical signs (days 4-5 post transfer). Unresponsiveness was shown to be dose-dependent, dependent on the route of injection of the neuroantigen-coupled splenocytes, and was antigen-specific. Splenocytes coupled with GP or rat MBP (which are identical within the major encephalitogenic GP68-86 Lewis rat determinant with the exception of the residue at position 80) were equally efficient at eliminating disease expression in recipients of GPMBP-specific T cells. In contrast, splenocytes coupled with bovine or rabbit MBP (which differ significantly from GPMBP within the 68-86 region) had no inhibitory effect. The antigen specificity of the tolerance induction was also illustrated by the fact that splenocytes coupled with GP68-86, but not those coupled with the truncated GP68-84 peptide, induced profound unresponsiveness. Interestingly, de novo antigen processing by the antigen-coupled cells did not appear to be necessary as the inclusion of antigen processing inhibitors had no effect on inhibition of disease. However, the use of the carbodiimide coupling reagent was critical for the induction of unresponsiveness as essentially equivalent amounts of 125I-labelled MBP were bound in its presence or absence, but only splenocytes incubated in the presence of both MBP and carbodiimide inhibited clinical expression of disease. Antigen-specific tolerance is thus an effective means of inhibiting expression of clinical disease in the rat EAE model, and a powerful tool for determining the fine epitope specificity of encephalitogenic T cells.

Animals↗
PubMed1987

[Effect of regulator cells induced by the influenza virus in adoptive transfer].

The protective effect of humoral and cellular immunity factors on experimental mouse influenza infection was studied in combination with a simultaneous analysis of the functional activity in the regulatory lymphocytes of donor mice. The efficacy of adoptive defense of recipient mice, that is the intensity of immune reactions in their organisms, was found to depend on the concrete functional state of donor mouse transferring cells. The exact time of activation of T-helper cells open certain prospects for the concrete pathogenetically grounded drug therapy.

Animals↗
PubMed1995

Adoptive transfer of ex vivo-activated memory T-cell subsets with cyclophosphamide provides effective tumor-specific chemoimmunotherapy of advanced metastatic murine melanoma and carcinoma.

Autolymphocyte therapy (ALT) is adoptive cellular therapy of neoplastic disease using ex vivo activation of autologous (human) or syngeneic (murine) lymphocytes from tumor-bearing hosts (TBH) by low doses of anti-CD3 monoclonal antibody (MAb) and a mixture of previously prepared autologous cytokines (T3CS). Ex vivo activation by T3CS without tumor antigen results in expansion of CD44+ (memory) T cells. These memory T cells (ALT cells) mediate in vivo anti-tumor specificity and with cyclophosphamide (CY) are capable of curing metastatic disease in murine TBH. To determine whether CY could enhance the effectiveness of CD4+ or CD8+ subsets of ALT cells, C57BL/6J TBH with B16 melanoma or Lewis lung (3LL) carcinoma were treated with adoptive chemoimmunotherapy (ACIT) using CD4-depleted or CD8-depleted ALT cells and CY. ALT cells were derived from splenocytes of B16 or 3LL-TBH and activated ex vivo with T3CS. Depletion of CD4+ or CD8+ T cells was performed before or after activation with T3CS. B16-TBH or 3LL-TBH that received ACIT using CY with B16-derived or 3LL-derived CD8-depleted ALT cells, respectively, demonstrated cure of metastatic disease regardless of whether CD8+ T cells were depleted before or after T3CS activation. B16 or 3LL-TBH that received ACIT using CY with B16 or 3LL-derived CD4-depleted ALT cells also cured metastatic disease but only if CD4+ T cells were depleted after T3CS activation. Interleukin (IL)-2 added to pre-T3CS CD4-depleted ALT cells cultured with T3CS restored anti-tumor activity when combined with CY. TBH cured by ACIT using CY and ALT-cell subsets derived from syngeneic TBH with the identical tumor displayed tumor-specific immunity in rejecting a lethal challenge of identical but not reciprocal tumor. TBH given ACIT using CY and ALT-cell subsets derived from splenocytes of syngeneic TBH with reciprocal tumors rejected lethal challenges of both tumors. Tumor specificity measured by interferon (IFN)-gamma and 51Cr-release assays was demonstrated in pre- or post-T3CS/CD8-depleted, post-T3CS/CD4-depleted and pre-T3CS + IL-2/CD4-depleted ALT-cell subsets. Our data demonstrate that ACIT using CY combined with ex vivo T3CS-activated CD44+ memory T-cell subsets conveys long-term tumor-specific immunity.

Animals↗
PubMedDate not supplied

Tissue distribution of adoptively transferred adherent LAK cells: role of the route of administration.

The ability of LAK and adherent LAK (A-LAK) cells to migrate to and localize into tumors might be a limiting factor for the efficacy of adoptive immunotherapy. Employing different routes of inoculation of A-LAK cells labeled with 125IUdR, we have investigated how murine A-LAK cells circulate in the bloodstream and localize into various tissues. After intravenous injection, most of the A-LAK cells migrated to the lungs with less than 15% redistributing to other organs. Following left ventricular inoculation, after which the injected cells do not have to pass the lung capillaries before reaching other organs, higher numbers of A-LAK cells were found in liver, carcass, kidney and gut compared to intravenous injection. However, most of the A-LAK cells were cleared from these organs within 24 h, and surprisingly at this time the overall survival of the injected A-LAK cells was not more than 10-20% regardless of the route of injection. We found that a substantial accumulation of A-LAK cells in the liver could be achieved only when the cells were injected directly into the portal vein. Following this route of administration, more than 40% of the injected A-LAK cells were still in the liver at 24 h, whereas only 3-5% had redistributed to other organs. Our data suggest that A-LAK cells circulate inefficiently and survive poorly following systemic administration. However, enhanced accumulation of these cells in a particular organ might be achieved by direct administration of the A-LAK cells into the vessels feeding the organ.

Animals↗