Insights from integrating clinical and preclinical studies advance understanding of graft-versus-host disease
Gérard Socié, … , Robert Zeiser, Bruce R. Blazar
Gérard Socié, … , Robert Zeiser, Bruce R. Blazar
Published June 8, 2021
Citation Information: J Clin Invest. 2021;131(12):e149296. https://doi.org/10.1172/JCI149296.
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Review

Insights from integrating clinical and preclinical studies advance understanding of graft-versus-host disease

Abstract

As a result of impressive increases in our knowledge of rodent and human immunology, the understanding of the pathophysiologic mechanisms underlying graft-versus-host disease (GVHD) has dramatically improved in the past 15 years. Despite improved knowledge, translation to clinical care has not proceeded rapidly, and results from experimental models have been inconsistent in their ability to predict the clinical utility of new therapeutic agents. In parallel, new tools in immunology have allowed in-depth analyses of the human system and have recently been applied in the field of clinical GVHD. Notwithstanding these advances, there is a relative paucity of mechanistic insights into human translational research, and this remains an area of high unmet need. Here we review selected recent advances in both preclinical experimental transplantation and translational human studies, including new insights into human immunology, the microbiome, and regenerative medicine. We focus on the fact that both approaches can interactively improve our understanding of both acute and chronic GVHD biology and open the door to improved therapeutics and successes.

Authors

Gérard Socié, Leslie S. Kean, Robert Zeiser, Bruce R. Blazar

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Figure 1

Comparing current and proposed schema for drug development in GVHD.

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Comparing current and proposed schema for drug development in GVHD. (A) ...
(A) Current schema for drug development in GVHD. As of today, new therapeutics are mostly based on scientific findings derived from experimental models that either test a drug or use a knockout system to assess the role of a given pathway in GVHD. These experimental results trigger the development of phase I and II clinical trials and eventually lead to the conduction of randomized trials. Example candidates resulting from such a process are depicted. It is of note that very few ancillary studies coming from clinical trials lead to further mechanistic studies in experimental models. (B) We proposed a shift in the paradigm of drug development in GVHD treatment wherein clinical development can either come from animal models or are derived from human samples. In all cases, results from clinical trials can generate novel hypothesis that need to be tested experimentally.