Immunotoxins: a surprisingly less toxic approach to stem cell transplants

Author: Holly Wobma, 07/06/16
Electron microscope image of blood cells (courtesy of wiki commons)

Electron microscope image of blood cells (courtesy of wiki commons)

It is often the case that to produce something ‘shiny,’ new and better, we must first get rid of the old. This is true even in the case of stem cell therapies.

Hematopoietic stem cell (HSC) transplants have been around since the mid-twentieth century and are used to treat a broad range of diseases such as leukemias and inherited blood disorders. Depending on the situation, the HSCs come from the patient (autologous) or from another donor (allogeneic). In both scenarios, however, the transplant is often preceded by a conditioning regimen to eliminate the problematic HSCs residing in the bone marrow and to create a more optimal environment for newly transplanted HSCs to engraft.

Traditionally, conditioning regimens have consisted of total body irradiation (TBI) and/or chemotherapeutic drugs. These treatments are especially toxic to dividing cells – like HSCs – but they have many adverse side effects due to their non-cell specific nature. Furthermore, since HSCs are the precursors to all blood cells, when they are eliminated it can leave the patient anemic and with little capacity to combat infection until the transplanted replacements start producing white blood cells again. Pathogens that would usually be innocuous suddenly can have life-threatening potential.

Motivated by this, Dr. David Scadden’s group, out of Massachusetts General Hospital, has developed a more targeted method based on “immunotoxins,” which was recently published in Nature Biotechnology. The “immune” part of the name comes from the fact that antibodies are used to bind to specific cell surface proteins. The “toxin” comes from the fact that these antibodies are linked to an enzyme called saporin (SAP), which kills cells by inhibiting their capacity for protein synthesis. Since the toxin is only internalized by cells when attached to the targeting antibody, very specific cell toxicity results.

Dr. Scadden’s group initially tested seven candidate antibodies that recognize HSC surface proteins in both mice and humans. Based on their in vivo screens in mice, they determined that CD45 specific immunotoxins (CD45-SAP) most effectively depleted bone marrow HSCs. They then performed a series of in vivo studies comparing CD45-SAP to the more conventional method of TBI.

They found that CD45-SAP was able to promote engraftment of transplanted HSCs, but it caused less damage to bone marrow architecture. It also caused less damage to other tissues, such as the thymus, which showed atrophy upon exposure to TBI. Since the thymus is a main source of T-cell production, the authors suggest that its relative preservation via CD45-SAP conditioning may explain why the T-cell population recovered much faster post-HSC transplant than when TBI was used (12 days vs. 48 days, respectively). Other immune cell types also recovered faster with CD45-SAP conditioning, an achievement that could have life or death implications.

In fact, the authors demonstrated this by exposing their variably conditioned mice to Candida albicans, a yeast that poses a severe threat to immunocompromised patients receiving HSC transplants. Whereas the TBI mice had 100% lethality by three days, most mice conditioned with CD45-SAP survived out to 50 days in a similar manner to the unconditioned control group.

Overall, the authors show their regimen enables effective HSC engraftment with reduced morbidity and risk for mortality. Since HSC transplantation can be potentially curative for a number of disorders, and its potential applications have been growing with recent progress in gene editing strategies, an immunotoxin approach may make this type of treatment more amenable to widespread use.

 

The following two tabs change content below.
Holly Wobma

Holly Wobma

MD/PhD student at Columbia University
Holly is an MD-PhD student at Columbia University in New York. She recently (2011) completed a Bachelor of Health Sciences Honours Degree from the University of Calgary, where she pursued research related to nanotechnology and regenerative medicine. In addition to research, she enjoys participating in science outreach roles. Previously, she contributed to an award-winning Nanoscience animation produced by the Science Alberta Foundation (“Do You Know What Nano Means?”), and served on the board of directors for the Canadian Institute for Photonic Innovations Student Network. Holly's lab tweets @GVNlab.
Tags: , , , , , , , , , , , ,

Leave a Reply

*
*