Spontaneous onset and transplant models of the Vk*MYC mouse show immunological sequelae comparable to human multiple myeloma.

Rachel E Cooke,Rachel Koldej,Dale I Godfrey,Miles Prince,Simon J Harrison,Hang Quach,David S Ritchie,Nicholas A Gherardin

doi:10.1186/s12967-016-0994-6

Abstract

BackgroundThe Vk*MYC transgenic and transplant mouse models of multiple myeloma (MM) are well established as a research tool for anti-myeloma drug discovery. However, little is known of the immune response in these models. Understanding the immunological relevance of these models is of increasing importance as immunotherapeutic drugs are developed against MM.MethodsWe set out to examine how cellular immunity is affected in Vk*MYC mouse models and compare that to the immunology of patients with newly diagnosed and relapsed/refractory MM.ResultsWe found that there were significant immunological responses in mice developing either spontaneous (transgenic) or transplanted MM as a consequence of the degree of tumor burden. Particularly striking were the profound B cell lymphopenia and the expansion of CD8+ effector memory T cells within the lymphocyte population that progressively developed with advancing disease burden, mirroring changes seen in human MM. High disease burden was also associated with increased inflammatory cytokine production by T lymphocytes, which is more fitting with relapsed/refractory MM in humans.ConclusionsThese findings have important implications for the application of this mouse model in the development of MM immunotherapies.Trial registration LitVacc ANZCTR trial ID ACTRN12613000344796; RevLite ANZCTR trial ID NCT00482261

Highlights

The Vk*MYC transgenic and transplant mouse models of multiple myeloma (MM) are well established as a research tool for anti-myeloma drug discovery
We found that the immunological consequences of disease in the Vk*MYC mouse models were similar whether spontaneous onset or transplant models were used, providing that macroscopically evident extramedullary disease was not present
Transgenic and transplant Vk*MYC mouse models show differing disease dynamics, but consistently develop B lymphopenia with advanced disease MM patients requiring treatment for their disease have organ damage in the form of anaemia, renal failure and/ or lytic bone lesions, which has been shown to be replicated in the Vk*MYC mouse models [16]

Summary

Introduction

The Vk*MYC transgenic and transplant mouse models of multiple myeloma (MM) are well established as a research tool for anti-myeloma drug discovery. Numerous factors in MM are involved in the velocity of disease progression and they are acquired in a nonstochastic but cumulative fashion over time [13]. These include immune-editing and oncogenic mutations, which both promote evasion from immune surveillance and. By utilizing knowledge of driver mutations, mouse models of disease have been developed. These mouse models are useful tools to study antimyeloma therapies; a deeper appreciation of their relevance to clinical disease is required. Less is known about the immunological similarities and differences between human disease and the Vk*MYC mouse models

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Discussion

Conclusion