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The Immunology, Inflammation, Infection, and Transplantation Research Theme (I3T)

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The Immunology, Inflammation, Infection, and Transplantation Research Theme (I3T)

Chronic Transplant Rejection

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  2. Immunology
  3. Transplantation Research
  4. Chronic Transplant Rejection

Can we halt chronic transplant rejection before it starts?

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Elaine F. Reed, PhD
Director, UCLA Immunogenetics Center

Professor, Department of Pathology & Laboratory Medicine, David Geffen School of Medicine at UCLA

Ending Chronic Transplant Rejection

Dr. Elaine F. Reed established that chronic transplant rejection results from an antibody-mediated immune response—not only the T cell immune response most researchers were studying.

Faced with chronic rejection, patients must receive a new organ or return to dialysis. In some cases, chronic rejection leads to death.

Dr. Reed hopes for a future where patients have functional transplants for life. She is working toward that future by trying to stop the antibody-mediated rejection signaling pathway at its origin.

Isolating—and Stopping—the Immune Mechanisms Behind Chronic Rejection

After a transplantation, patient antibodies sometimes attack the mismatched human leukocyte antigens (HLA) of the donor organ. Once the attack begins, it is nearly impossible to turn off with drug-based treatments. That's why Dr. Reed's lab wants to stop immune initiation at its most proximate point.

"By targeting these interactions most proximately, at the top of the pyramid, we can block all the negative downstream events triggered by the early immune response," says Dr. Reed.

By studying antibody-mediated immune responses in vitro, in animal models, and in human tissue, Dr. Reed’s team has defined several critical mechanisms of chronic rejection.

 

See Discovery and Implication Use Cases

Discovery: An antibody-mediated response is focused in the endothelium.

Antibodies activate the endothelia and cause alterations in their function. Once endothelia become dysfunctional, the transplant can experience inflammation and chronic injury. Read more in HLA Class II-Triggered Signaling Cascades Cause Endothelial Cell Proliferation and Migration: Relevance to Antibody-Mediated Transplant Rejection, published in the Journal of Immunology.

Implication: Knowing the immune activation pathway, the team could better focus their studies and achieve the next big breakthrough.

 

Discovery: A specific molecular partnership triggers an immune response against a transplant.

Focusing on the endothelium, Dr. Reed and her team uncovered a signaling pathway triggered by mismatched human leukocyte antigens on the donor organ. The pathway enables endothelial cell activation and proliferation, leading to organ injury and rejection. Read more in HLA Class I Molecules Partner with Integrin β4 to Stimulate Endothelial Cell Proliferation and Migration, published in Science Signaling.

Implication: The finding gave researchers a pathway they might block to protect transplants from immune attack.

Dr. Reed and her team are testing drugs to block immune effector functions while continuing to explore additional immune initiation pathways contributing to transplant rejection.

UCLA Pathology & Laboratory Medicine

The Future of Bench-to-Bedside Transplant Rejection Research

In addition to researching ways to stop rejection, Dr. Reed is also developing ways to better diagnose and treat the chronic rejection we cannot stop.

Dr. Reed developed a biomarker panel that allows physicians to determine if a patient is suffering from rejection without taking biopsies, which can be painful, costly, and sometimes deadly. If commercialized, the panel could soon be available to facilities everywhere. Read more in Apolipoprotein A1 and C-terminal fragment of a-1 antichymotrypsin are candidate plasma biomarkers associated with acute renal allograft rejection, published in Transplantation.

Dr. Reed leads a research team using precision medicine techniques to study cytomegalovirus (CMV), a common herpes virus that can damage transplants and devastate immunocompromised patients. Backed by $8 million from the National Institute of Allergy and Infectious Diseases, the team plans to map the molecular processes of CMV infection to better assess patient risks and develop optimal treatments.

Dr. Reed believes we can improve patient health by constantly testing novel interventions to tame the most damaging aspects of transplant rejection. That doesn’t stop her from dreaming of a future without rejection.

"Imagine telling a child transplant recipient that she'll have her new organ for a lifetime. That would be the most important thing we could do in transplant," says Dr. Reed.

Help patients keep transplants for life by supporting immunology research →

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