Featured Research

from universities, journals, and other organizations

How common chemo drug thwarts graft rejection in bone marrow transplants

Date:
November 13, 2013
Source:
Johns Hopkins Medicine
Summary:
Results of a study may explain why a chemotherapy drug called cyclophosphamide prevents graft-versus-host (GVHD) disease in people who receive bone marrow transplants. The experiments point to an immune system cell that evades the toxic effects of cyclophosphamide and protects patients from a lethal form of GVHD.

Results of a Johns Hopkins study may explain why a chemotherapy drug called cyclophosphamide prevents graft-versus-host (GVHD) disease in people who receive bone marrow transplants. The experiments point to an immune system cell that evades the toxic effects of cyclophosphamide and protects patients from a lethal form of GVHD.

The findings, published online Nov. 13 in Science Translational Medicine, could pave the way for improvements in preventing GVHD and rejection of transplanted bone marrow and new therapies to prevent or treat a relapse of the underlying cancer after a transplant.

"Finding the optimal conditions to avoid interfering with immune cells working to eradicate cancer while preventing graft rejection and GVHD is the holy grail of bone marrow transplant," says Leo Luznik, M.D., associate professor of oncology at the Johns Hopkins Kimmel Cancer Center. "We've known for some time that giving cyclophosphamide after a transplant helps prevent GVHD, and our study provides an important piece of the puzzle for why it works."

GVHD occurs when newly transplanted immune cells from a donor's bone marrow attack the patient's body. Commonly used immunosuppressant drugs prevent rapid-onset, acute GVHD but not persistent, long-lasting, chronic GVHD, which may cause severe disability and death.

In the early 2000s, Johns Hopkins scientists Leo Luznik and Ephraim Fuchs found that giving patients high doses of cyclophosphamide -- a drug derived from nitrogen mustard and used to treat blood cancers -- three days after bone marrow transplant successfully thwarts acute and chronic GVHD. Johns Hopkins physicians also found that post-transplant cyclophosphamide enabled safe administration of new, half-matched bone marrow transplants in addition to traditional, fully matched ones. Medical centers around the world now use the Johns Hopkins protocol of post-transplant cyclophosphamide, and Luznik says the inexpensive drug is becoming increasingly mainstream in bone marrow transplant regimens.

Some of the first clues to how cyclophosphamide works were also discovered in the 1980s by Johns Hopkins scientists. They found that cyclophosphamide kills all of the donor's transplanted bone marrow cells except for stem cells containing high levels of an enzyme called aldehyde dehydrogenase (ALDH). The ALDH-laden stem cells evade the toxic effects of cyclophosphamide and rebuild the patient's immune system. Richard Jones, M.D., professor and director of the Bone Marrow Transplant Program at Johns Hopkins, developed a now commonly used assay to study ALDH levels in individual cells.

Yet, scientists lacked an explanation for why post-transplant cyclophosphamide effectively curtailed acute and chronic GVHD.

Luznik and his team inventoried types of immune cells present in the blood of bone marrow transplant patients treated with post-transplant cyclophosphamide. The scientists zeroed in on a type of immune cell called regulatory T-cells, which were known to suppress autoimmune responses. They found high levels of the regulatory T-cells in patients treated with post-transplant cyclophosphamide, and lab-cultured cells survived cyclophosphamide treatment. Using polymerase chain reaction methods that amplify DNA and Jones' assay that detects by-products of ALDH, the Johns Hopkins team found that regulatory T-cells express high levels of ALDH.

"These regulatory T-cells are resistant to post-transplant cyclophosphamide and likely subdue the autoimmune-like response of the donor's bone marrow, preventing GVHD," says Christopher Kanakry, M.D., first author of the study and clinical fellow at the Johns Hopkins Kimmel Cancer Center. Patients receiving standard immunosuppressive drugs after transplant, as opposed to high-dose cyclophosphamide, have slower recovery of regulatory T-cells in their blood, adds Kanakry.

The scientists also showed, in lab-cultured human cells, that an ALDH-blocking drug strips regulatory T-cells of their ability to grow and protect themselves from cyclophosphamide.

Luznik says his team is continuing to study methods to improve post-transplant cyclophosphamide, and it may be possible to use these findings to add other relapse-fighting therapies early after transplant. "Our findings may also lead to even wider acceptance of post-transplant cyclophosphamide," he said.


Story Source:

The above story is based on materials provided by Johns Hopkins Medicine. Note: Materials may be edited for content and length.


Journal Reference:

  1. C. G. Kanakry, S. Ganguly, M. Zahurak, J. Bolanos-Meade, C. Thoburn, B. Perkins, E. J. Fuchs, R. J. Jones, A. D. Hess, L. Luznik. Aldehyde Dehydrogenase Expression Drives Human Regulatory T Cell Resistance to Posttransplantation Cyclophosphamide. Science Translational Medicine, 2013; 5 (211): 211ra157 DOI: 10.1126/scitranslmed.3006960

Cite This Page:

Johns Hopkins Medicine. "How common chemo drug thwarts graft rejection in bone marrow transplants." ScienceDaily. ScienceDaily, 13 November 2013. <www.sciencedaily.com/releases/2013/11/131113143133.htm>.
Johns Hopkins Medicine. (2013, November 13). How common chemo drug thwarts graft rejection in bone marrow transplants. ScienceDaily. Retrieved July 31, 2014 from www.sciencedaily.com/releases/2013/11/131113143133.htm
Johns Hopkins Medicine. "How common chemo drug thwarts graft rejection in bone marrow transplants." ScienceDaily. www.sciencedaily.com/releases/2013/11/131113143133.htm (accessed July 31, 2014).

Share This




More Health & Medicine News

Thursday, July 31, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Health Insurers' Profits Slide

Health Insurers' Profits Slide

Reuters - Business Video Online (July 30, 2014) Obamacare-related costs were said to be behind the profit plunge at Wellpoint and Humana, but Wellpoint sees the new exchanges boosting its earnings for the full year. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com
Concern Grows Over Worsening Ebola Crisis

Concern Grows Over Worsening Ebola Crisis

AFP (July 30, 2014) Pan-African airline ASKY has suspended all flights to and from the capitals of Liberia and Sierra Leone amid the worsening Ebola health crisis, which has so far caused 672 deaths in Guinea, Liberia and Sierra Leone. Duration: 00:43 Video provided by AFP
Powered by NewsLook.com
At Least 20 Chikungunya Cases in New Jersey

At Least 20 Chikungunya Cases in New Jersey

AP (July 30, 2014) At least 20 New Jersey residents have tested positive for chikungunya, a mosquito-borne virus that has spread through the Caribbean. (July 30) Video provided by AP
Powered by NewsLook.com
Xtreme Eating: Your Daily Caloric Intake All On One Plate

Xtreme Eating: Your Daily Caloric Intake All On One Plate

Newsy (July 30, 2014) The Center for Science in the Public Interest released its 2014 list of single meals with whopping calorie counts. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

    Environment News

    Technology News



      Save/Print:
      Share:

      Free Subscriptions


      Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

      Get Social & Mobile


      Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

      Have Feedback?


      Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
      Mobile: iPhone Android Web
      Follow: Facebook Twitter Google+
      Subscribe: RSS Feeds Email Newsletters
      Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins