Prospective Studies Of The Effect Of Antibody Reduction In Preventing Chronic Rejection

Paul Terasaki, Mikki Ozawa, Matthew Everly

In the 13th, 14th and 15th Workshops, over 90 worldwide transplant labs submitted data on antibody tests on post-transplant sera, which totaled to 12,647 kidney, 609 heart, 511 liver, and 242 lung transplant patients.  Each study consistently showed that antibodies are highly predictive of chronic rejection.  By 4 years after the antibody testing, 29% of the kidney patients with antibodies had graft loss, compared to 14% in patients without antibodies (see Figure 1), and this was also shown in heart (Figure 2), lung (Figure 3), and liver transplants.  This means that HLA antibodies do cause graft rejection in these transplants.

The three Workshop studies also showed that it takes a long time for the antibodies to cause damage, and that the donor-specific antibodies (DSA) were most detrimental.  Now that we have these evidence and knowledge, we can strategize the next important step – to treat the antibodies before they cause damage, and ultimately eliminate chronic rejection.

Study Proposal:
In order to achieve our goal, we propose using the drug Velcade (bortezomib) to treat the antibodies.  This drug, which has been used to treat multiple myloma patients, was found to be effective in reducing antibodies as recently shown by Dr. Matthew Everly at this year’s TTS meeting in Sydney.  We have additional convincing data that Velcade has a great potential.  Our plan is to screen patients for antibodies, and if donor-specific antibodies were found, treat them with Velcade.  This treatment will have less side effects than inceasing the dose of conventional immunosuppressive drugs.  

Outline of plan:

1. Collect post-transplant sera from patients who currently have functioning graft.
2. Test for antibodies and determine whether they are DSA.  (We will supply the antibody screening and Single Antigen reagents).
3. Identify patients with antibodies to be treated   
4. Treat with Bortizumib protocol after taking a reference sample (detailed protocol and Human Subject Protection Justification to be furnished.)
5. Monitor post-treatment patients for DSA levels by Single Antigen testing.
6. Compare the graft survival of patients successfully treated with positive patients who were not treated and patients who did not have antibodies.
7. Individual centers can publish results, but a summary will be planned for the 16th International Histocompatibility Workshop in England, which we hope you will attend.
   

Attachments:

1. Patient registration form
2. Four year prospective trial paper on kidneys
3. Bortezomib therapy paper by M. Everly

Contacts:
Please let us know if you would like to participate in the workshop.  We will provide you with further information as the project proceeds.

Paul Terasaki, Mikki Ozawa, Matthew Everly
Terasaki Foundation Laboratory,
Los Angeles,
CA  90064,
USA

Email: terasaki [at] terasakilab [dot] org or mozawa [at] terasakilab [dot] org.

Download a PDF of the ASHI 2010 Presentation - download PDF file.

Download a PDF of the EFI 2011 Presentation - download PDF file.

Download a PDF of the ASHI 2011 Presentation - download PDF file.

Nov 10, 2011 Posted by Admin