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Spontaneous Post-Transplant Disorders in NOD.Cg- Prkdcscid Il2rgtm1Sug/JicTac (NOG) Mice Engrafted with Patient-Derived Metastatic Melanomas.

Radaelli E, Hermans E, Omodho L, Francis A, Vander Borght S, Marine JC, van den Oord J, Amant F - PLoS ONE (2015)

Bottom Line: Affected mice exhibited extensive scaling/crusting dermatitis (13/14) associated with emaciation (13/14) and poor/unsuccessful tumor engraftment (14/14).In this context, the following pathological conditions have been recognized and characterized in details: (i) immunoinflammatory disorders with features of graft versus host disease (14/14); (ii) reactive lymphoid infiltrates effacing xenografted tumors (8/14); (iii) post-transplant B cell lymphomas associated with Epstein-Barr virus reactivation (2/14).On the other hand, the evidence of an immune response of human origin against the xenotransplanted melanoma opens intriguing perspectives for the establishment of suitable preclinical models of anti-melanoma immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: VIB11 Center for the Biology of Disease, KU Leuven Center for Human Genetics, Leuven, Belgium; InfraMouse, KU Leuven-VIB, Leuven, Belgium.

ABSTRACT
Patient-derived tumor xenograft (PDTX) approach is nowadays considered a reliable preclinical model to study in vivo cancer biology and therapeutic response. NOD scid and Il2rg-deficient mice represent the "gold standard" host for the generation of PDTXs. Compared to other immunocompromised murine lines, these mice offers several advantages including higher engraftment rate, longer lifespan and improved morphological and molecular preservation of patient-derived neoplasms. Here we describe a spectrum of previously uncharacterized post-transplant disorders affecting 14/116 (12%) NOD.Cg- Prkdcscid Il2rgtm1Sug/JicTac (NOG) mice subcutaneously engrafted with patient-derived metastatic melanomas. Affected mice exhibited extensive scaling/crusting dermatitis (13/14) associated with emaciation (13/14) and poor/unsuccessful tumor engraftment (14/14). In this context, the following pathological conditions have been recognized and characterized in details: (i) immunoinflammatory disorders with features of graft versus host disease (14/14); (ii) reactive lymphoid infiltrates effacing xenografted tumors (8/14); (iii) post-transplant B cell lymphomas associated with Epstein-Barr virus reactivation (2/14). We demonstrate that all these entities are driven by co-transplanted human immune cells populating patient-derived tumor samples. Since the exploding interest in the utilization of NOD scid and Il2rg-deficient mice for the establishment of PDTX platforms, it is of uppermost importance to raise the awareness of the limitations associated with this model. The disorders here described adversely impact tumor engraftment rate and animal lifespan, potentially representing a major confounding factor in the context of efficacy and personalized therapy studies. The occurrence of these conditions in the NOG model reflects the ability of this mouse line to promote efficient engraftment of human immune cells. Co-transplanted human lymphoid cells have indeed the potential to colonize the recipient mouse initiating the post-transplant conditions here reported. On the other hand, the evidence of an immune response of human origin against the xenotransplanted melanoma opens intriguing perspectives for the establishment of suitable preclinical models of anti-melanoma immunotherapy.

No MeSH data available.


Related in: MedlinePlus

Atypical plasma cell-rich lymphoid infiltrates of donor origin in NOG mice xenotransplanted with human metastatic melanoma are monoclonal and reflect the development of post-transplant B cell/plasma cell malignancies associated with Epstein-Barr virus (EBV) reactivation.(A) The atypical plasma cell-rich infiltrates show kappa light chain restriction suggesting monoclonal B cell/plasma cell expansion. Kappa and Lambda light immunoglobulin chains immunohistochemistry, scale bar = 100 μm. (B) Atypical lymphoid infiltrates show a clear monoclonal pattern for all IgH and IgK frameworks confirming the development of post-transplant B cell/plasma cell neoplasms, fragment lenght for each monoclonal peak is indicated (left). On the contrary, matched original human tumor biopsy displays a polyclonal pattern which is consistent with the presence of reactive B cells/plasma cells (right). Multiplex PCR for IgH and IgK rearrangements. (C) Approximately 30–40% of the atypical B cells/plasma cells populating the monoclonal lymphoid proliferation display a strong EBV-encoded RNA (EBER1-2) hybridization signal (left). On the contrary no EBER1-2 signal is observed in the original tumor biopsy (right) suggesting a post-transplant reactivation of EBV. EBER1-2 in situ hybridization, scale bar = 100 μm.
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pone.0124974.g005: Atypical plasma cell-rich lymphoid infiltrates of donor origin in NOG mice xenotransplanted with human metastatic melanoma are monoclonal and reflect the development of post-transplant B cell/plasma cell malignancies associated with Epstein-Barr virus (EBV) reactivation.(A) The atypical plasma cell-rich infiltrates show kappa light chain restriction suggesting monoclonal B cell/plasma cell expansion. Kappa and Lambda light immunoglobulin chains immunohistochemistry, scale bar = 100 μm. (B) Atypical lymphoid infiltrates show a clear monoclonal pattern for all IgH and IgK frameworks confirming the development of post-transplant B cell/plasma cell neoplasms, fragment lenght for each monoclonal peak is indicated (left). On the contrary, matched original human tumor biopsy displays a polyclonal pattern which is consistent with the presence of reactive B cells/plasma cells (right). Multiplex PCR for IgH and IgK rearrangements. (C) Approximately 30–40% of the atypical B cells/plasma cells populating the monoclonal lymphoid proliferation display a strong EBV-encoded RNA (EBER1-2) hybridization signal (left). On the contrary no EBER1-2 signal is observed in the original tumor biopsy (right) suggesting a post-transplant reactivation of EBV. EBER1-2 in situ hybridization, scale bar = 100 μm.

Mentions: In 2 out of the 14 animals affected by xenogeneic GVHD-like condition, we observed plasma cell-rich lymphoid infiltrates with findings of marked cytologic atypia (i.e. anisocytosis, anisokaryosis, cytomegaly, karyomegaly, multinucleation and increased numbers of mitoses with aberrant mitotic figures) expanding the mediastinum and renal hilum, respectively (Fig 4). Also in these cases, IHC for human-specific MHC class I and mouse-specific CD45 LCA confirmed the human origin of the atypical infiltrates. Lesions were also immunostained for Melan A, HMB45 and Tyrosinase but no positive cells were detected ruling out a possible combination between atypical metastatic melanoma cells accompanied by dense plasma cell-rich lymphoid infiltrates. On the contrary, atypical infiltrates were diffusely positive for markers of mature B cell/plasma cell differentiation (i.e. CD20, PAX5, BLIMP1, CD138 and MUM1p) (Fig 4) and showed kappa immunoglobulin light chain restriction suggesting a monoclonal expansion (Fig 5). In addition, plasma cells populating the atypical lesions showed an aberrantly high proliferative index as highlighted via duplex Ki67 and CD138 immunofluorescence (S5 Fig). The monoclonal nature of these atypical mature B cell/plasma cell proliferations/infiltrates was further demonstrated at molecular level (i.e. PCR for IGH and IGL loci rearrangement). Clonality profiles from mouse lesions and matched original tumors are presented in Fig 5. In both the atypical murine lymphoid infiltrates/proliferations, we observed a clear monoclonal pattern for IGH and IGK. Representative tissue samples with plasma cell-rich lymphoid infiltrates, considered reactive based on microscopic examination, were also selected (as controls) from NOG mice suffering from xenogeneic GVHD-like condition and confirmed to be polyclonal.


Spontaneous Post-Transplant Disorders in NOD.Cg- Prkdcscid Il2rgtm1Sug/JicTac (NOG) Mice Engrafted with Patient-Derived Metastatic Melanomas.

Radaelli E, Hermans E, Omodho L, Francis A, Vander Borght S, Marine JC, van den Oord J, Amant F - PLoS ONE (2015)

Atypical plasma cell-rich lymphoid infiltrates of donor origin in NOG mice xenotransplanted with human metastatic melanoma are monoclonal and reflect the development of post-transplant B cell/plasma cell malignancies associated with Epstein-Barr virus (EBV) reactivation.(A) The atypical plasma cell-rich infiltrates show kappa light chain restriction suggesting monoclonal B cell/plasma cell expansion. Kappa and Lambda light immunoglobulin chains immunohistochemistry, scale bar = 100 μm. (B) Atypical lymphoid infiltrates show a clear monoclonal pattern for all IgH and IgK frameworks confirming the development of post-transplant B cell/plasma cell neoplasms, fragment lenght for each monoclonal peak is indicated (left). On the contrary, matched original human tumor biopsy displays a polyclonal pattern which is consistent with the presence of reactive B cells/plasma cells (right). Multiplex PCR for IgH and IgK rearrangements. (C) Approximately 30–40% of the atypical B cells/plasma cells populating the monoclonal lymphoid proliferation display a strong EBV-encoded RNA (EBER1-2) hybridization signal (left). On the contrary no EBER1-2 signal is observed in the original tumor biopsy (right) suggesting a post-transplant reactivation of EBV. EBER1-2 in situ hybridization, scale bar = 100 μm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4440639&req=5

pone.0124974.g005: Atypical plasma cell-rich lymphoid infiltrates of donor origin in NOG mice xenotransplanted with human metastatic melanoma are monoclonal and reflect the development of post-transplant B cell/plasma cell malignancies associated with Epstein-Barr virus (EBV) reactivation.(A) The atypical plasma cell-rich infiltrates show kappa light chain restriction suggesting monoclonal B cell/plasma cell expansion. Kappa and Lambda light immunoglobulin chains immunohistochemistry, scale bar = 100 μm. (B) Atypical lymphoid infiltrates show a clear monoclonal pattern for all IgH and IgK frameworks confirming the development of post-transplant B cell/plasma cell neoplasms, fragment lenght for each monoclonal peak is indicated (left). On the contrary, matched original human tumor biopsy displays a polyclonal pattern which is consistent with the presence of reactive B cells/plasma cells (right). Multiplex PCR for IgH and IgK rearrangements. (C) Approximately 30–40% of the atypical B cells/plasma cells populating the monoclonal lymphoid proliferation display a strong EBV-encoded RNA (EBER1-2) hybridization signal (left). On the contrary no EBER1-2 signal is observed in the original tumor biopsy (right) suggesting a post-transplant reactivation of EBV. EBER1-2 in situ hybridization, scale bar = 100 μm.
Mentions: In 2 out of the 14 animals affected by xenogeneic GVHD-like condition, we observed plasma cell-rich lymphoid infiltrates with findings of marked cytologic atypia (i.e. anisocytosis, anisokaryosis, cytomegaly, karyomegaly, multinucleation and increased numbers of mitoses with aberrant mitotic figures) expanding the mediastinum and renal hilum, respectively (Fig 4). Also in these cases, IHC for human-specific MHC class I and mouse-specific CD45 LCA confirmed the human origin of the atypical infiltrates. Lesions were also immunostained for Melan A, HMB45 and Tyrosinase but no positive cells were detected ruling out a possible combination between atypical metastatic melanoma cells accompanied by dense plasma cell-rich lymphoid infiltrates. On the contrary, atypical infiltrates were diffusely positive for markers of mature B cell/plasma cell differentiation (i.e. CD20, PAX5, BLIMP1, CD138 and MUM1p) (Fig 4) and showed kappa immunoglobulin light chain restriction suggesting a monoclonal expansion (Fig 5). In addition, plasma cells populating the atypical lesions showed an aberrantly high proliferative index as highlighted via duplex Ki67 and CD138 immunofluorescence (S5 Fig). The monoclonal nature of these atypical mature B cell/plasma cell proliferations/infiltrates was further demonstrated at molecular level (i.e. PCR for IGH and IGL loci rearrangement). Clonality profiles from mouse lesions and matched original tumors are presented in Fig 5. In both the atypical murine lymphoid infiltrates/proliferations, we observed a clear monoclonal pattern for IGH and IGK. Representative tissue samples with plasma cell-rich lymphoid infiltrates, considered reactive based on microscopic examination, were also selected (as controls) from NOG mice suffering from xenogeneic GVHD-like condition and confirmed to be polyclonal.

Bottom Line: Affected mice exhibited extensive scaling/crusting dermatitis (13/14) associated with emaciation (13/14) and poor/unsuccessful tumor engraftment (14/14).In this context, the following pathological conditions have been recognized and characterized in details: (i) immunoinflammatory disorders with features of graft versus host disease (14/14); (ii) reactive lymphoid infiltrates effacing xenografted tumors (8/14); (iii) post-transplant B cell lymphomas associated with Epstein-Barr virus reactivation (2/14).On the other hand, the evidence of an immune response of human origin against the xenotransplanted melanoma opens intriguing perspectives for the establishment of suitable preclinical models of anti-melanoma immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: VIB11 Center for the Biology of Disease, KU Leuven Center for Human Genetics, Leuven, Belgium; InfraMouse, KU Leuven-VIB, Leuven, Belgium.

ABSTRACT
Patient-derived tumor xenograft (PDTX) approach is nowadays considered a reliable preclinical model to study in vivo cancer biology and therapeutic response. NOD scid and Il2rg-deficient mice represent the "gold standard" host for the generation of PDTXs. Compared to other immunocompromised murine lines, these mice offers several advantages including higher engraftment rate, longer lifespan and improved morphological and molecular preservation of patient-derived neoplasms. Here we describe a spectrum of previously uncharacterized post-transplant disorders affecting 14/116 (12%) NOD.Cg- Prkdcscid Il2rgtm1Sug/JicTac (NOG) mice subcutaneously engrafted with patient-derived metastatic melanomas. Affected mice exhibited extensive scaling/crusting dermatitis (13/14) associated with emaciation (13/14) and poor/unsuccessful tumor engraftment (14/14). In this context, the following pathological conditions have been recognized and characterized in details: (i) immunoinflammatory disorders with features of graft versus host disease (14/14); (ii) reactive lymphoid infiltrates effacing xenografted tumors (8/14); (iii) post-transplant B cell lymphomas associated with Epstein-Barr virus reactivation (2/14). We demonstrate that all these entities are driven by co-transplanted human immune cells populating patient-derived tumor samples. Since the exploding interest in the utilization of NOD scid and Il2rg-deficient mice for the establishment of PDTX platforms, it is of uppermost importance to raise the awareness of the limitations associated with this model. The disorders here described adversely impact tumor engraftment rate and animal lifespan, potentially representing a major confounding factor in the context of efficacy and personalized therapy studies. The occurrence of these conditions in the NOG model reflects the ability of this mouse line to promote efficient engraftment of human immune cells. Co-transplanted human lymphoid cells have indeed the potential to colonize the recipient mouse initiating the post-transplant conditions here reported. On the other hand, the evidence of an immune response of human origin against the xenotransplanted melanoma opens intriguing perspectives for the establishment of suitable preclinical models of anti-melanoma immunotherapy.

No MeSH data available.


Related in: MedlinePlus