Indiana University-Purdue University Indianapolis

IUPUI - Department of Mathematical Sciences

Topic 1:

Mathematical Modeling of the Immune-Mediated Rejection of Transplants - Julia Arciero, with Giorgio Raimondi (John Hopkins School of Medicine)

Organ transplantation is a life-saving surgical procedure through which the functionality of a failing organ system can be restored.  Transplants are performed for a wide variety of organs, including skin, heart, kidney, liver, pancreas, spleen, and lung. However, without the administration of immunosuppressive drugs, the recipient’s immune system recognizes the transplanted tissue as a foreign and potentially dangerous material and responds with a massive immune attack that ultimately destroys the graft.  This massive immune response represents a major roadblock in the development of effective therapeutic regimens for patients requiring organ transplants, as demonstrated by the current absence of a clinically effective therapy and the need to rely on chronic immunosuppression.

Previous hypothesis-driven experimental work has provided important insight into the interactions among multiple immunological components.  However, the observed complexity of the immune response motivates the use of an integrated theoretical and experimental approach to unravel the inter-connected components of the immune response that contribute to transplant rejection.  While several computational models have been previously implemented to predict the dynamics of the immune system in response to viral or bacterial infections, no theoretical models have been developed in the field of transplant rejection.  The objective of this project is to develop a theoretical model to predict how the dynamics of the immune response influence the rejection of an organ transplant and to identify new and effective strategies to promote transplant tolerance that could then be experimentally investigated.  This objective will be achieved through the following two specific aims:

  1. To develop a mathematical model of the immune-mediated rejection of transplants.  The model will include a lymph node compartment and a graft compartment.  The model will be used to simulate interactions between the immune system and graft cells immediately following transplantation and to identify pathways that can be targeted for possible therapies to modulate transplant rejection.
  2. To calibrate the theoretical model with experimental data on the dynamics of components of the transplant rejection response.  A mouse model of skin transplantation and a widely used model based on transgenic cells will be implemented to measure parameters (e.g. infiltration and activation of immune cells) necessary to calibrate and optimize the model developed in Aim 1 and to test the validity of model predictions.

Topic 2:

Modeling and simulation of interstitial fluid flow over an osteocyte - Louding Zhu

As one of the most important human organs, bones serve multiple functions through complex external and internal structures. A keen understanding of how bone works at all levels is crucial to our health. For example, osteoporosis and fracture due to lack of physical activity (in seniors, the bedridden, and even inactive youth) have become an increasingly severe, worldwide healthcare problem. Bone is somehow able to remodel via mechanical loading (eg, from physical exercise), regulating bone growth, decay, and healing. Osteocytes, which reside in the mineralized bone matrix are responsible for mechanotransduction: the conversion of mechanical stimuli into biochemical signals, leading to either bone formation or degradation. Despite intensive studies, it remains a mystery as to how mechanical forces are sensed by the osteocyte. In particular, it is unclear which part/organelle of the cell actually perceives mechanical stimuli.

The other enigma is that the level of strain/stress that can induce responses in an osteocyte is found to be about 10 times greater than that at the tissue level. Therefore, the strain/stress at tissue level are somehow amplified by 10 times at the cellular level by the fluid-osteocyte lacuno-canalicular (FOLC) system. To date, the relevant principles/mechanisms have yet to be identified.

Although in vitro experiments have been conducted extensively, they are not yet able to directly measure desired mechanical variables, such as fluid wall shear stress (WSS) or force distribution/concentration. In contrast, in silico (modeling and simulation), has become an indispensable alternative complementing experiments. Our project aims to introduce physiologically realistic computational models taking into account most physiological factors. Our goal is to understand the mechanisms/principles of the stress/strain magnification of the fluid-osteocyte lacuno-canalicular system in vivo by means of modeling and simulation, in tandem with ex vivo experiments.