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Sickle cell disease is an inherited red cell disorder affecting an estimated 100,000 individuals in the U.S and millions worldwide. It’s caused by a single genetic mutation that affects the shape of the oxygen carrying red blood cells, making it difficult for the red blood cells to get through small blood vessels. In turn, the cells clog blood flow and cut off oxygen delivery to the organs.

Studies led by New York Blood Center Enterprise’s (NYBCe) Karina Yazdanbakhsh, PhD, have found that the hemolytic stress resulting from hemoglobin and its byproducts can alter the behavior of major immune cell types as well as cells in the bone marrow, worsening the sickle cell complications. These same cell types are impacted by transfusions, a lifesaving treatment for patients with sickle cell disease.

Dr. Yazdanbakhsh heads NYBCe’s Laboratory of Complement Biology and is a member of the nonprofit’s research division, the Lindsley F. Kimball Research Institute (LFKRI). With the help of a multi-disciplinary research team and a $15.6M five-year grant, she hopes to fill the gaps in our knowledge about sickle cell disease to advance our understanding of transfusion outcomes and develop novel approaches to improve transfusion efficacy for those with the disorder.

The investigator recently sat down with NYBCe representatives to talk more about her research on sickle cell disease as well as her legacy with the organization.

Q: Congratulations on your recent $15.6M five-year grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health! How large of an impact does funding of this magnitude have on your research and what do you hope to accomplish by the end of 5 years?

Lindsley F. Kimball Research Institute researcher Karina Yazdanbakhsh, PhD

Dr. Yazdanbakhsh: We are honored and humbled to have received this grant. This award, in essence, recognizes the gaps in our knowledge and how little we understand about why transfusions are life-saving for some patients with sickle cell disease, but can be ineffective or life-threatening in others.

With this award, our collaborative research group can tackle the problem in a more comprehensive manner, from understanding how various immune cell types — which are key to disease pathology — are impacted by the disease in various organs and tissues to investigating whether transfusions by reversing the disease trajectories can improve the disease.

Our goal is to have at the minimum a deeper molecular understanding of immune pathways affected in this disease and after transfusion along with candidate drugs and improved transfusion protocols for better management of the disease.

Q: Sickle cell disease is caused by a genetic mutation that changes the shape of red blood cells, thereby reducing their lifespan, clogging blood vessels, and causing anemia. You’ve mentioned how the degradation of these red blood cells can even affect immune cells in the bone marrow. Can you explain what relationship blood transfusions have to these issues and how your research will investigate them?

Dr. Yazdanbakhsh: The bone marrow in an adult is where red blood cells are produced from stem cells. Investigators in the field, in particular our own Dr. Mohan Narla, have known that immune cells in the bone marrow are critical for helping stem cells become red cells.

LFKRI’s Dr. Xiuli An has now identified what that immune cell is. Patients with sickle cell disease are anemic, and as a result their bone marrow is under constant pressure to produce new red blood cells, including the immune cells that help stem cells to become red cells.

However, sickle red cells are fragile and they can fall apart, releasing their content into the bloodstream. These breakdown products are in fact toxic and can destroy any cell or tissue they land on or are taken up. We hypothesize that these sickle red cell breakdown products will also be toxic to the cells in bone marrow, including the immune cells supporting red blood cell development.

Another key collaborator on this project is LFKRI’s Dr. Avital Mendeslon who is studying key bone marrow cell types which support hematopoietic stem cell quality. We hypothesize that these cells, called mesenchymal stem cells, are affected adversely by the red cell content released in the bone marrow environment in sickle cell disease, affecting the health of the sickle stem cells.

By increasing the number of healthy red cells, transfusions relieve the stress on the bone marrow to produce red blood cells. Our research led by Dr. An is investigating how the immune cell that supports the stem cell to become red blood cells is impacted by the red cell breakdown product, and if this causes worsening of the anemia in sickle cell disease and reversed by transfusions. In parallel, Dr. Mendelson is examining the sickle bone marrow to identify the molecular profiles of mesenchymal and hematopoietic stem cells affected in sickle cell disease and how transfusions may be improving these particular cell types.

These studies will pave the way to use targeted therapies that improve the function of these immune cells to improve bone marrow environment of the patients prior to transplant or gene therapies.

Q: What implications do you think this research will have in the long term for sickle cell patients?

Dr. Yazdanbakhsh: Developing optimal transfusion therapy protocols or even tailored transfusion regimens for each patient to maximize the known benefits of transfusions while minimizing potential risk of adverse reactions.

The long-term goals of our research also includes the development of cell-based therapies and novel drugs that can be used at the time of transfusions to unclog the blood vessels in patients with sickle cell disease or further lower the risk of transfusion-related adverse events.

Our research aims to develop immune biomarkers so that we can identify in advance which patients are at risk of transfusion reactions and reserve the fully-matched blood products, which are rare, for these patients to avoid potential reactions. By understanding at the molecular level how transfusions work, we can expand the use of transfusions to prevent or treat many complications of sickle cell disease or limit their use.

Compared to 5 years ago, we now have several new drugs for sickle cell disease. While the life-saving properties of transfusions for patients with sickle cell disease are likely to be complex, our multi-prong approach of studying how they work in the various tissues of these patients may one day lead to the development of a “transfusion pill” which is as effective as transfusions.

Q: NYBCe has created a Sickle Cell Information Center where people can stay up to date on your team’s research. Of the publications you’ve released, are there any that you’d consider “must-reads” for those interested in learning more?

Dr. Yazdanbakhsh: Here are four that I would recommend!

Hemolysis inhibits humoral B-cell responses and modulates alloimmunization risk in patients with sickle cell disease.
Pal M, Bao W, Wang R, Liu Y, An X, Mitchell WB, Lobo CA, Minniti C, Shi PA, Manwani D, Yazdanbakhsh K, Zhong H.
Blood. 2021 Jan 14;137(2):269-280. doi: 10.1182/blood.2020008511.
PMID: 33152749

Patrolling monocytes scavenge endothelial-adherent sickle RBCs: a novel mechanism of inhibition of vaso-occlusion in SCD.
Liu Y, Zhong H, Bao W, Mendelson A, An X, Shi P, Chou ST, Manwani D, Yazdanbakhsh K.
Blood. 2019 Aug 15;134(7):579-590. doi: 10.1182/blood.2019000172. Epub 2019 May 10.
PMID: 31076443 Free PMC article.

Altered heme-mediated modulation of dendritic cell function in sickle cell alloimmunization. 
Godefroy E, Liu Y, Shi P, Mitchell WB, Cohen D, Chou ST, Manwani D, Yazdanbakhsh K.
Haematologica. 2016 Sep;101(9):1028-38. doi: 10.3324/haematol.2016.147181. Epub 2016 May 26.
PMID: 27229712 Free PMC article.

Hemin controls T cell polarization in sickle cell alloimmunization. 
Zhong H, Bao W, Friedman D, Yazdanbakhsh K.
J Immunol. 2014 Jul 1;193(1):102-10. doi: 10.4049/jimmunol.1400105. Epub 2014 May 30.
PMID: 24879794 Free PMC article.

How I safely transfuse patients with sickle-cell disease and manage delayed hemolytic transfusion reactions.
Pirenne F, Yazdanbakhsh K.
Blood. 2018 Jun 21;131(25):2773-2781. doi: 10.1182/blood-2018-02-785964. Epub 2018 May 3.
PMID: 29724898 Free PMC article. Review.

Q: Let’s take a step back and look at your career with the Enterprise. How long have you been with NYBCe? And which areas of research have you primarily focused on during that time?

Dr. Yazdanbakhsh: I’ve been with New York Blood Center Enterprises for 25 years now. Mainly, my research has focused on understanding the immune response to transfusions and blood components in patients with blood disorders.

Q: Does your current research differ from your initial areas of interest? If so, how did your research evolve to this topic? What motivates you to continue pursuing this subject?

Dr. Yazdanbakhsh: I was trained as a molecular biologist, and my initial research interests were focused on understanding how genes are regulated within a specific tissue or cell type and in response to various cues including immune stimuli. As my research has evolved, the focus has shifted to immunological responses to transfusions and blood components in specific disease states.

I am motivated to figure out how an individual’s immune system works, and what is unique in the immune system of patients with hemoglobinopathies with the goal of optimizing their  transfusion management and developing immune-based therapies or treatments to ultimately help improve patient care.

Q: How has conducting your research via NYBCe and LFKRI propelled your research forward?

Dr. Yazdanbakhsh: My research is primarily in transfusion immunology and, at NYBCe, I am surrounded not only by leaders in transfusion medicine and blood banking, but I also benefit daily from my interactions with LFKRI top hematologists, and infectious disease experts.

Our recent grant, for example, was funded in part because of established close collaboration with our LFKRI colleagues as well as with medical and blood operations. Access to blood components including high quality white blood cells from every racial and ethnic background, our unique cord blood inventory, our unparalleled leadership and expertise in transfusion medicine and cellular therapies, and our wealth of red cell reagents has been invaluable help for my studies.

Q: Back to your current research. How has your research been affected by the COVID-19 pandemic, if at all?

Dr. Yazdanbakhsh: Our program with patient-related research was affected. In the summer of 2020, we saw patients slowly coming back to participate in our research. By early December, though, patients retreated. I’m hopeful that we will be seeing an uptick as more patients are vaccinated.

Recruiting good postdoctoral candidates from outside New York has also been exceptionally challenging, but we have plans in place.

Q: How can the general audience help support your research?

Dr. Yazdanbakhsh: Research funding remains highly competitive and difficult to secure. I urge you to help fund our research programs which are unique lines of investigation dedicated to improving patient care for patients with sickle cell disease.

As a nonprofit, New York Blood Center Enterprises relies on philanthropy to support different aspects of their life-saving mission, from daily operations to groundbreaking blood research.

If you’d like to support Dr. Yazdanbakhsh’s research on sickle cell disease or any other projects conducted by LFKRI investigators, please consider giving online now. You can also contact the Office of Philanthropy directly to learn more about the organization’s philanthropic needs.

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