Transcript Bild 1 - AbSorber AB

AbSorber
 Rejection & Graft Survival
 XM-ONE®
A Challenge in Organ Transplantation
Optimizing Patient & Graft Survival
Rejection and Graft Survival
Acute rejection has become less likely to be reversed fully, and
many patients develop irreversible damage after an episode of
rejection*
The consequences of ARE are depending of**
References:
*Flavio Vincenti,
Clin J Am Soc Nephrol
1: 399-, 2006
** Gerhard Opelz,
Transplantation
2008;85: 661–666
Timing of ARE
Type of ARE
Severity of ARE
S-Creatinine reduction after ARE
Number of ARE’s
Acute Rejection predicts impaired halflife
Reference:
Hariharan, S et al: N Engl
J Med; Vol342, No 9, 2000
Pretransplant antibodies influence graft
failure
Reference:
Gerhard Opelz for the
Collaborative
Transplant Study*
Lancet 2005; 365: 1570–76
Degree of Immunization in HLA-identical
siblings
• The PRA activity in HLA
identical siblings is
associated with poorer
graft survival
• These findings further
supports the role of
non-HLA antibodies
Reference: Gerhard Opelz
for the Collaborative
Transplant Study*
Lancet 2005; 365:
1570–76
CTS Conclusions
Significant association between pretransplant HLA
antibodies and outcome of kidney grafts from diseased
donors.
In the study of HLA identical siblings a similar
association was seen.
”When the long-term results for kidney recipients
with PRA were examined over 10 years of followup, the influence of non-HLA-directed immunity
was of similar magnitude to that of antibodies
against HLA”
Reference:
Gerhard Opelz for the
Collaborative
Transplant Study*
Lancet 2005; 365: 1570–76
Non-HLA antibodies associated
with graft rejections
SPECIFICITIES OF NON-HLA ANTIBODIES WITH RELEVANCE IN ORGAN TRANSPLANTATION
SPECIFICITY
TYPE OF REJECTION
REFERENCES
EC reactive abs. against vimentin, desmin-Heart tx
AR
2, 3
EC specifi c abs. against a 100 kD antigen Kidney tx
HAR, AR
1
EM specifi c antibodies (HMA-1 and HMA-2) Kidney tx
HAR, AR
10
EC reactive abs. against MICA Kidney tx
EGL, AR
7–9
Tissue-specifi c abs. Agrin Kidney tx
CR
4
Abs. to Angiotensin II type-1 Receptor Kidney tx
VR
5
Abs. to α-Gal Xeno tx
HAR
6
AR: Acute rejections; HAR: hyperacute rejections; EGL: early graft loss; CR: chronic rejection; VR: vascular rejection.
1. Sumitran-Karuppan S et al, Transpl Immunol 1997, 5:321-327. 2. Carter V, et al: Transplant Proc 2005, 37:654-657.
3. Jurcevic Set al Transplantation 2001, 71:886-892. 4. Joosten SA, et al. Am J Transplant 2005, 5:383-393. 5. Dragun D,
et al; N Engl J Med 2005, 352:558-569. 6. Lucq J, et al;Xenotransplantation 2000, 7:3. 7. Zwirner NW, et al; Human
Immunol 2000, 61:917-924. 8. Stastny P: Hum Immunol 2006, 67:141-144. 9. Sumitran-Holgersson S et
al.Transplantation 2002, 74:268-277. 10. Jager MJ, et al; Hum Immunol 1987, 19:215-224.
Reference:
Suchitra SumitranHolgersson Current
Opinion in Immunology
2008, 20:607–613
Non-HLA Antibody Detection
There is a need for commercially available
methods for the reliable and reproducible
detection of non-HLA antibodies.
”As it becomes increasingly recognized that non-HLA
antibodies contribute significantly to antibodymediated processes, it will be important to find
reproducible assays for these antibodies such that
their prevalence and impact may be quantified
better.”
Reference:
Kathryn J. Tinckam,
and Anil Chandraker
Clin J Am Soc Nephrol
1: 404-414, 2006
And so it begun …… (at Huddinge
Hospital)
 A girl transplanted in 1993 *
- Abrupt graft failure (x3) due to Hyperacute
Rejection
 A boy transplanted in 1998
- Abrupt graft failure (x2) due to Hyperacute
Rejection
 Endothelial Antibodies detected i both
patients (through UVEC)
*Reference:
Sumitran-Karuppan S et al,
Transplant Immunology
1997;5:321-327
XM-ONE®
An Endothelial Crossmatch
 Introduction & Background
 Multicenter Study Data
XM-ONE® :
Detects antibodies against cell bound antigens
HLA I
non-HLA
Tie-2-r
HLA II
Peripheral blood endothelial cell precursor
Endothelial precursor cell
Magnetic bead coated
with anti- Tie-2 monoclonal
antibody
The XM-ONE® kit – Product code 362640 - contains the components to perform 4 tests:
The XM-ONE© testing procedure is similar
to that of lymphocyte flow cutometry cross
match tests.
Reference:
XM-ONE, package insert
Reading XM-ONE® by flow cytometry
R1 Gate on endothelial precursor cells
Reference:
XM-ONE, package insert
XM-ONE® prospective multicenter study
Multicenter evaluation of a novel endothelial cell crossmatch
test in kidney transplantation (Reference: Breimer et al;
Transplantation;87(4):549-556,February 27,2009.)
Michael E. Breimer, Lennart Rydberg, Annette M. Jackson, Donna P. Lucas,
Andrea A. Zachary, Joseph K. Melancon, Jon Von Visger, Ronald Pelletier,
Susan L. Saidman, Winfred W. Williams, Jr., Jan Holgersson, Gunnar Tydén,
Göran K. Klintmalm, Sonnya Coultrup, Suchitra Sumitran-Holgersson
and Per Grufman
Study Design
- multicenter clinical study with XM-ONE®
Recruitment
Patient Information
Lymphocyte
crossmatch (LXM)
Endothelial Cell
crossmatch
(XM-ONE)
n=147
Clinical follow-up
> 3 month / rejection
Study Design:
Reference: Breimer et al;
Transplantation.
87(4):549-556,
February 27, 2009.

Decisions about transplantation and immunosuppressive treatment
based on results from LXM and solid phase assay

If a rejection episode occured responsible staff was informed about
XM-ONE results before making decisions about immunosuppressive
treatment
Study Centres and Investigators
Reference: Breimer et al;
Transplantation.
87(4):549-556,
February 27, 2009.
Baylor University Med Center
Dallas, TX, USA
Göran B. Klintmalm
Sonnya Coultrup
Ohio State University Med Center
Columbus, OH, USA
Ron M. Pelletier
Jon von Visger
Johns Hopkins University
Baltimore, MD, USA
Donna Lucas
Andrea A. Zachary
Annette Jackson
J.K. Melancon
Massachusetts General Hospital
Boston, MA, USA
Winfred W. Williams Jr.
Susan L. Saidman
Karolinska Institute, Huddinge
Hospital, Stockholm, Sweden
Jan Holgersson
Gunnar Tyden
Suchitra Sumitran-Holgersson
Sahlgrenska University Hospital
Gothenburg, Sweden
Michael E. Breimer
Lennart Rydberg
AbSorber
Per Grufman
XM-ONE® positive patients experienced
rejections early after transplantation
Reference: Breimer et al;
Transplantation.
87(4):549-556,
February 27, 2009.
Reference: Breimer et al; Transplantation. 87(4):549-556, February 27, 2009.
XM-ONE® positive crossmatch is
associated with an increased rate of
rejections
Patients
n=147
Reference: Breimer et al;
Transplantation.
87(4):549-556,
February 27, 2009.
Rejections
19,7%
(29 / 147)
XM-ONE® positive
46%
(16 / 35)
p <0,0005
XM-ONE® negative
12%
(13 / 112)
All C4d positive rejections occured in
XM-ONE® positive patients
Reference: Breimer et al;
Transplantation.
87(4):549-556,
February 27, 2009.
Reference: Breimer et al; Transplantation. 87(4):549-556, February 27, 2009.
Creatinine levels were significantly
higher in XM-ONE® positive patients
p < 0,05
Reference: Breimer et al;
Transplantation.
87(4):549-556,
February 27, 2009.
p < 0,05
Reference: Breimer et al; Transplantation. 87(4):549-556, February 27, 2009.
XM-ONE® positive patients experience
rejections also in the absence of donor
specific HLA antibodies
Rejection Frequency
XM-ONE®
Lymphocyte
Flow Cytometry
Crossmatch*
Reference: Breimer et al;
Transplantation.
87(4):549-556,
February 27, 2009.
Positive
Negative
Positive
4/7
(57%)
0/7
(0%)
Negative
10 / 24
(42%)
11 / 75
(15%)
* Not all patients were tested with Lymphocyte Flow Cytometry Crossmatch
Conclusions
 XM-ONE® positive patients experience significantly more
rejections then XM-ONE® negative patients
 XM-ONE® positive patients experienced earlier and more severe
rejections then XM-ONE® negative patients
 XM-ONE® positive patients have higher creatinine values at 3
and 6 months after transplantation
 XM-ONE® positive patients experience rejection episodes also in
spite of negative Lymphocyte crossmatch
Reference: Breimer et al;
Transplantation.
87(4):549-556,
February 27, 2009.
Oxford Study
Preliminary data from recipients of living
donor renal transplants (n=22).
• HLA and MICA antibody screening: Luminex
• Standard PBL crossmatches: complement dependent
cytotoxicity (CDC) and flow cytometry (FC).
• XM-ONE® EPC crossmatch: FC using patient serum and cells
isolated with XM-ONE®
Reference: J Procter, M Ray,
J Agudelo, A Muthusamy,
PJ Friend, KJ Wood,
SV Fuggle EFI20092009.
Results
• Allogeneic PBL CDC and FC Crossmatch:
All patients negative
• Allogeneic XM-ONE® Crossmatch:
6/22 (27%) patients IgM positive
3/22 (14%) patients IgG positive
All IgG+ patients included in IgM+ group
Reference: J Procter, M Ray,
J Agudelo, A Muthusamy,
PJ Friend, KJ Wood,
SV Fuggle EFI20092009.
Post transplant creatinine levels
• Significant difference in the change in serum creatinine
levels (µmol/L) between 1-3 and 1-6 months post
transplant between groups
• Creatinine levels improved in the XM-ONE negative , but
not in the XM-ONE positive patients
Reference:
J Procter, M Ray,
J Agudelo, A Muthusamy,
PJ Friend, KJ Wood,
SV Fuggle EFI 2009
Conclusion
• In 22 LD recipients negative in CDC and FC crossmatch 6
patients (27%) were found positive with the XM-ONE test
• No difference was seen regarding incidence of acute
rejections (1 / 6 XM-ONE positive patient, 1 / 16 XM-ONE
negative patient)
• S-creatinine was significantly increased in the XM-ONE
positive patients both at three (p<0,02) and six months
(p<0,04) post transplant compared to the one month value
Reference: J Procter, M Ray,
J Agudelo, A Muthusamy,
PJ Friend, KJ Wood,
SV Fuggle EFI20092009.
• The results from the Oxford XM-ONE study gives further
support to the multicenter study published in Transplantation
Feb 27, 2009, by Breimer and co-workers
Conclusion (I)
 HLA antibodies are associated to rejections
 However, rejections are still present in ”HLA-alike”
and HLA –identical patients
 There are strong evidence that non-HLA antibodies
contributes to the occurence rejections
Conclusion (II)
 XM-ONE® identifies patients that have an increased
risk to develop rejections early after transplantation
 XM-ONE® provides the transplant team with
valuable information on the patients response to the
transplanted organ before it occurs
The XM-ONE® kit – Product code 362640 - contains the components to perform 4 tests: