Adoptive immunotherapy against kidney targets in dog-leukocyte antigen-identical mixed hematopoietic canine chimeras

Junghanß, Christian; Takatu, Alessandra; Little, Marie Térèse; Zaucha, Jan Maciej; Zellmer, Eustacia; Yunusov, Murad Y.; Sale, George E.; Georges, George E.; Storb, Rainer

doi:10.1097/01.tp.0000045224.52516.fc

Cited by 9 publications

(9 citation statements)

References 35 publications

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“…Previous immunotherapies in out-bred canines included mAbs, vaccines, and hematopoietic stem-cell transplantation2627. The large companion dog population and widespread prevalence of canine cancers can power pre-clinical human trials to determine feasibility, efficacy, and safety in order to expand our knowledge of applied cellular therapy28.…”

Section: Discussionmentioning

confidence: 99%

Adoptive T-cell therapy improves treatment of canine non–Hodgkin lymphoma post chemotherapy

O'Connor

Sheppard

Hartline

et al. 2012

Sci Rep

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Clinical observations reveal that an augmented pace of T-cell recovery after chemotherapy correlates with improved tumor-free survival, suggesting the add-back of T cells after chemotherapy may improve outcomes. To evaluate adoptive immunotherapy treatment for B-lineage non-Hodgkin lymphoma (NHL), we expanded T cells from client-owned canines diagnosed with NHL on artificial antigen presenting cells (aAPC) in the presence of human interleukin (IL)-2 and IL-21. Graded doses of autologous T cells were infused after CHOP chemotherapy and persisted for 49 days, homed to tumor, and significantly improved survival. Serum thymidine kinase changes predicted T-cell engraftment, while anti-tumor effects correlated with neutrophil-to-lymphocyte ratios and granzyme B expression in manufactured T cells. Therefore, chemotherapy can be used to modulate infused T-cell responses to enhance anti-tumor effects. The companion canine model has translational implications for human immunotherapy which can be readily exploited since clinical-grade canine and human T cells are propagated using identical approaches.

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Section: Discussionmentioning

confidence: 99%

Adoptive T-cell therapy improves treatment of canine non–Hodgkin lymphoma post chemotherapy

O'Connor

Sheppard

Hartline

et al. 2012

Sci Rep

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“…Because our canine mixed chimeras were DLA-antigen matched but minor antigen mismatched, successful engraftment of vascularized composite allografts was dependent on tolerance to non-MHC antigens shared between hematopoietic cells and the donor composite tissue graft. Non-MHC antigen disparities among dogs can cause potent rejections of skin (32), or kidney allografts (33,34) or cause GVHD (35). Organs that approach the skin in susceptibility to rejection are small bowel (36) and lung (37).…”

Section: Discussionmentioning

confidence: 99%

Tolerance to Vascularized Composite Allografts in Canine Mixed Hematopoietic Chimeras

et al. 2011

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Background Mixed donor-host chimerism, established through hematopoietic cell transplantation (HCT), is a highly reproducible strategy for the induction of tolerance towards solid organs. Here, we ask whether a nonmyeloablative conditioning regimen establishing mixed donor-host chimerism leads to tolerance of highly antigenic vascularized composite allografts. Methods Stable mixed chimerism was established in dogs given a sublethal dose (1–2 Gy) total body irradiation before and a short course of immunosuppression after dog leukocyte antigen-identical marrow transplantation. Vascularized composite allografts from marrow donors were performed after a median of 36 (range 4-54) months after HCT. Results All marrow recipients maintained mixed donor-host hematopoietic chimerism and accepted composite tissue grafts for periods ranging between 52 and 90 weeks; in turn, marrow donors rejected vascularized composite allografts from their respective marrow recipients within 18–29 days. Biopsies of muscle and skin of vascularized composite allografts from mixed chimeras showed few infiltrating cells compared to extensive infiltrates in biopsies of vascularized composite allografts from marrow donors. Elevated levels of CD3+ FoxP3+ T-regulatory cells were found in skin and muscle of vascularized composite allografts of mixed chimeras compared to normal tissues. In mixed chimeras, increased numbers of T-regulatory cells were found in draining compared to non-draining lymph nodes of vascularized composite allografts. Conclusion These data suggest that nonmyeloablative HCT may form the basis for future clinical applications of solid organ transplantation and that T-regulatory cells may function towards maintenance of the vascularized composite allograft.

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“…The kidney was maintained in cold heparinized saline while the recipient was prepared for surgery. The kidney was subsequently transplanted into the trichimeric recipient's right anterior thigh; the renal artery and vein were anastamosed to the femoral artery and vein, respectively; and the ureter was implanted into the bladder [8]. The kidney graft recipients received no immunosuppressive therapy.…”

Section: Kidney Transplantationmentioning

confidence: 99%

“…Previous work in our laboratory evaluated whether graft-versus-host (GVH) reactions, typically directed against hematopoietic cells, skin, gut, and liver, could be diverted to reliably include metastatic solid malignancies [8]. In these experiments, we used a canine HCT model in which the kidney served as a surrogate tumor target.…”

Section: Introductionmentioning

confidence: 99%

“…Stable mixed chimerism in this model was maintained by regulatory T cells [9,10] and could not be dislodged by infusion of naïve donor lymphocytes [11]. To shift mixed chimerism to all-donor chimerism and induce graft-versus-host disease (GVHD), donor lymphocytes were sensitized to host minor H antigens [8]. Accordingly, after mixed chimerism was established in donor lymphocyte antigen (DLA)-identical littermate recipients, the marrow donors underwent transplantation of kidneys from their respective mixed chimeric recipients, which they rejected within 3 to 5 weeks.…”

Section: Introductionmentioning

confidence: 99%

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Adoptive Immunotherapy Against Allogeneic Kidney Grafts in Dogs with Stable Hematopoietic Trichimerism

Graves

Diaconescu

Harkey

et al. 2008

Biology of Blood and Marrow Transplantation

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Dogs given nonmyeloablative conditioning and marrow grafts from two dog leukocyte antigen- (DLA) identical littermate donors developed stable trichimerism and stably accepted a subsequent kidney graft from one of the marrow donors without the need for immunosuppression. Here, we used trichimeras to evaluate strategies of adoptive immunotherapy to solid tumors, using the kidney as a tumor surrogate. Three DLA-identical trichimeric recipients were established by simultaneously infusing marrow from two DLA-identical donor dogs into a DLA-identical recipient conditioned with 2 Gy total body irradiation and given a short course of postgrafting immunosuppression. After confirming stable hematopoietic engraftment, a kidney was transplanted from one of the two marrow donors into each respective trichimeric recipient. Peripheral blood lymphocytes (PBL) from each kidney donor were then used to sensitize the alternate marrow donor. Donor lymphocyte infusions (DLI) from the sensitized dogs were given to the trichimeric recipients, whereupon chimerism, graft-versus-host disease (GvHD), and kidney rejection were monitored. After DLI, we observed both prompt rejection of the transplanted marrow-donor kidney and disappearance of corresponding hematopoietic chimerism. Presumably, owing to shared minor histocompatibility antigens, host chimerism also disappeared and GvHD in skin, gut, and liver developed. The native kidneys, while showing lymphocytic infiltration, remained functionally normal. The current study demonstrated that under certain experimental conditions, the kidney, an organ ordinarily not involved in graft-versus-host reactions, can be targeted by sensitized donor lymphocytes.

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Adoptive immunotherapy against kidney targets in dog-leukocyte antigen-identical mixed hematopoietic canine chimeras

Cited by 9 publications

References 35 publications

Adoptive T-cell therapy improves treatment of canine non–Hodgkin lymphoma post chemotherapy

Adoptive T-cell therapy improves treatment of canine non–Hodgkin lymphoma post chemotherapy

Tolerance to Vascularized Composite Allografts in Canine Mixed Hematopoietic Chimeras

Adoptive Immunotherapy Against Allogeneic Kidney Grafts in Dogs with Stable Hematopoietic Trichimerism

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