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Transplantation Immunology Current Status. Volker Daniel, MD Institute of Immunology, Department of Transplantation Immunology, University of Heidelberg, Im Neuenheimer Feld 305 D-69120 Heidelberg Germany [email protected] Transplantation Immunology.

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Transplantation immunology current status

Transplantation Immunology Current Status

Volker Daniel, MD

Institute of Immunology, Department of Transplantation Immunology, University of Heidelberg,

Im Neuenheimer Feld 305

D-69120 Heidelberg

Germany

[email protected]


Transplantation immunology
Transplantation Immunology

  • TPL (numbers, overview, history)

  • HLA

  • Preoperative tests (prophylaxis of rejection)

  • Mechanisms of rejection (solid organs)

  • Immunosuppression

  • Tolerance (induction)

  • Clinical complications (infection, cancer)

  • Bone marrow and stem cell transplantation

  • Xenotransplantation

  • Artifical organs


Transplantation immunology1
Transplantation Immunology

  • TPL (general aspects, numbers, overview, history)

  • HLA

  • Preoperative tests (prophylaxis of rejection)

  • Mechanisms of rejection (solid organs)

  • Immunosuppression

  • Tolerance (induction)

  • Clinical complications (infection, cancer)

  • Bone marrow and stem cell transplantation

  • Xenotransplantation

  • Artifical organs


Organ failure alternative treatment strategies
Organ FailureAlternative Treatment Strategies

Mechanical organ replacement

  • Dialysis, bioartificial liver, cardiovascular device

    Artificial organs

  • Tissue engineering, therapeutical cloning

    Organs of other species

  • Xenotransplantation


Benefit of transplantation
Benefit of Transplantation

  • nearly unrestricted quality of life

  • rehabilitated in profession and social relationships



Pioneers of transplantation
Pioneers of Transplantation

  • Joseph Murray (kidney, 1954)

  • James D. Hardy (lung, 1963)

  • Richard Lillehei (pancreas, 1966)

  • Christian Barnard (heart, 1967)

  • Thomas E. Starzl (liver, 1967)

  • Jean Dausset (HLA, 1958)

  • Jon van Rood (Eurotransplant, 1967)


International transplant records
International Transplant Records

Clinical Transplants 2001; 279-318




Transplantation immunology2
Transplantation Immunology

  • TPL (general aspects, numbers, overview, history)

  • HLA

  • Preoperative tests (prophylaxis of rejection)

  • Mechanisms of rejection (solid organs)

  • Immunosuppression

  • Tolerance (induction)

  • Clinical complications (infection, cancer)

  • Bone marrow and stem cell transplantation

  • Xenotransplantation

  • Artifical organs






Population studies show association of susceptibility to insulin-dependent diabetes mellitus (IDDM) with HLA genotype


Family studies show strong linkage of susceptibility to insulin-dependent diabetes mellitus (IDDM) with HLA genotype


Transplantation immunology3
Transplantation Immunology insulin-dependent diabetes mellitus (IDDM) with HLA genotype

  • TPL (general aspects, numbers, overview, history)

  • HLA

  • Preoperative tests (prophylaxis of rejection)

  • Mechanisms of rejection (solid organs)

  • Immunosuppression

  • Tolerance (induction)

  • Clinical complications (infection, cancer)

  • Bone marrow and stem cell transplantation

  • Xenotransplantation

  • Artifical organs


Microlymphocytotoxicity assay
Microlymphocytotoxicity Assay insulin-dependent diabetes mellitus (IDDM) with HLA genotype

Separation of lymphocytes using densitiy gradient centrifugation

Separation of lymphocytes in T and B cells using Dynabeads

Dotting lymphocytes on Terasaki microtrays predotted with HLA antisera, Incubation period of 30 min

Addition of rabbit serum (complement), Incubation period of 60 min

Addition of acridinorange and ethidiumbromide, Incubation period of 15 min

Fluorescence microscopy


Mikrolymphocytotoxicity test
Mikrolymphocytotoxicity test insulin-dependent diabetes mellitus (IDDM) with HLA genotype

Positive

Negative


Molecular based techniques for hla typing
Molecular-Based Techniques for HLA Typing insulin-dependent diabetes mellitus (IDDM) with HLA genotype

  • RFLP (Restriction Fragment Length Polymorphism)

  • PCR-SSO (PCR - Sequence Specific Oligonucleotide Hybridization)

    - Dot Blot (Standard Procedure) = amplified DNA is dotted

    - RDB (Reverse Dot Blot = oligos are dotted)

  • PCR-SSP (ARMS) (PCR - Sequence Specific Primers)

  • SBT (Sequence Based Typing)

  • PCR-RFLP u.a.


Hla typing degrees of resolution
HLA-Typing; Degrees of Resolution insulin-dependent diabetes mellitus (IDDM) with HLA genotype


Polymorphism of hla june 2006
Polymorphism of HLA insulin-dependent diabetes mellitus (IDDM) with HLA genotypeJune 2006

http://www.ebi.ac.uk/imgt/hla/stats.html


Full List of HLA-A, -B, and -DR alleles (2 digits) assigned as of April 2003

http://www.anthonynolan.com/HIG/nomenc.html




Meyer M, Czachurski D, Tran TH, Opelz G, Mytilineos J. as of April 2003

A new PCR-SSP typing method for six single-nucleotide polymorphisms impairing the blood-clotting cascade as well as T-cell stimulation.Tissue Antigens. 2005 Dec;66(6):650-5.

Czachurski D, Scollo A, Skambraks A, Perichon AM, Scherer S, Tran TH, Opelz G, Grappiolo I, Mytilineos J.

Description and characterization of two new HLA alleles, B*4051 and DRB1*1364, identified by sequence-based typing.Tissue Antigens. 2005 Aug;66(2):151-5.

Czachurski D, Scherer S, Gehrke S, Laux G, Opelz G, Mytilineos J.

Identification of two new HLA alleles: B*3546* and B*5611*. How reliable are the published HLA-B intron 2 sequences?Tissue Antigens. 2004 Oct;64(4):500-5.

Czachurski D, Opelz G, Mytilineos J.

A new HLA-DRB allele (DRB1*15014) identified in a Caucasian individual.Hum Immunol. 2003 Feb;64(2):310-3.

Czachurski D, Rausch M, Scherer S, Opelz G, Mytilineos J.

Characterization of a new HLA-A allele, A*0256, identified in a Caucasian individual.Tissue Antigens. 2002 Aug;60(2):180-3.


Lancet as of April 2003. 2005 Apr 30-May 6;365(9470):1570-6.

Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies.Opelz G; Collaborative Transplant Study.


Figure 2.  as of April 200310-year follow-up of kidney grafts from HLA-identical sibling donors


Transplantation as of April 2003. 2002 Apr 27;73(8):1269-73.

Kidney graft failure and presensitization against HLA class I and class II antigens.Susal C, Opelz G.


Figure 1 as of April 2003. Influence of ELISA-detected pretransplant IgG-anti-HLA class I and class II antibodies on cadaver kidney graft survival. Recipients possessing both anti-HLA class I and class II antibodies (I+/II+) had a significantly lower graft survival rate than antibody-negative recipients (I-/II-) (log-rank P <0.0001). Anti-HLA class I-positive/class II-negative (I+/II-) and anti-HLA class I-negative/class II-positive recipients (I-/II+) showed surprisingly good graft success rates.


N Engl J Med as of April 2003. 1994 Mar 24;330(12):816-9.

The influence of HLA compatibility on graft survival after hearttransplantation. The Collaborative Transplant Study.Opelz G, Wujciak T.


Figure 1. as of April 2003 Actuarial Survival Rates of First Heart Transplants According to the Number of HLA-A, B, or DR Mismatches. The numbers of mismatched antigens and the numbers of grafts studied are indicated for each curve.


Eurotransplant
Eurotransplant as of April 2003

The Eurotransplant International Foundation is responsible for the

mediation and allocation of organ donation procedures in

  • Austria

  • Belgium

  • Germany

  • Luxemburg

  • The Netherlands

  • Slovenia

    In this international collaborative framework, the participants include all transplant hospitals, tissue-typing laboratories and hospitals where organ donations take place. The Eurotransplant region numbers well over 118 million inhabitants.


Transplantation centers
Transplantation Centers as of April 2003


Dialysis patients on waiting list
Dialysis Patients on Waiting List as of April 2003

  • ABO blood group

  • HLA-A, -B, -C, -DR, -DQ alleles

  • Panel reactive antibodies


Dialysis patients on waiting list1
Dialysis Patients on Waiting List as of April 2003

Every 3 months serum screening for HLA antibodies

Results to Eurotransplant

Sera of immunized patients shipped to transplantation centers for future crossmatches


Sensitization against hla antigens
Sensitization Against HLA Antigens as of April 2003

  • Previous Transplantation

  • Pregnancy

  • Blood Transfusions

  • Virus Infections


Sensitization of dialysis patients
Sensitization of Dialysis Patients as of April 2003

Sensitization Number of Patients (n=358)

  • 0% 282

  • 1-10% 33

  • 11-20% 13

  • 21-30% 6

  • 31-40% 5

  • 41-50% 7

  • 51-60% 4

  • 61-70% 2

  • 71-80% 2

  • 81-90% 2

  • 91-100% 1


Retransplants kidney
Retransplants (Kidney) as of April 2003

Previous Transplants Number of Patients (n=358)

0 293

1 49

2 16

3 0


Cross talk
Cross Talk as of April 2003

Eurotransplant

Donor Center Recipient Center

HLA Typing Lab


Kidney donor
Kidney Donor as of April 2003

ABO blood group and HLA typing

Results to Eurotransplant

Crossmatch list from ET with prospective recipients

Crossmatches

Results to ET

Patient with negative crossmatch and highest score receives kidney


Criteria for kidney allocation
Criteria for Kidney Allocation as of April 2003

  • ABO blood group

  • Compatibility in HLA-A, -B, and -DR alleles

  • HLA mismatch probability

  • Waiting time

  • Preservation time

  • National organ exchange balance


Priority
Priority as of April 2003

  • Children (<16 years of age)

  • Patients immunized against HLA antigens

  • High urgency patients

  • Patients with combined transplantations


Kidney donor1
Kidney Donor as of April 2003

ABO blood group and HLA typing

Results to Eurotransplant

Crossmatch list from ET with prospective recipients

Crossmatches

Results to ET

Patient with negative crossmatch and highest score receives kidney



Preservation time
Preservation Time as of April 2003

  • Kidney 24 - 72 hours

  • Heart 4 - 8 hours

  • Liver - 24 hours

  • Pancreas - 12 hours

  • Lung - 6 hours



Methods of transplantation
Methods of Transplantation Host)

  • Cellular transplant: injection of cell suspension

  • free transplant: no vascular anastomosis

  • stemmed transplant: temporary vascular stem, removed after take of the graft

  • organ transplantation: vascular anastomosis


Location of the transplant
Location of the Transplant Host)

  • orthotopic: at the original location

  • heterotopic: at another location


Transplantation immunology4
Transplantation Immunology Host)

  • TPL (general aspects, numbers, overview, history)

  • HLA

  • Preoperative tests (prophylaxis of rejection)

  • Mechanisms of rejection (solid organs)

  • Immunosuppression

  • Tolerance (induction)

  • Clinical complications (infection, cancer)

  • Bone marrow and stem cell transplantation

  • Xenotransplantation

  • Artifical organs


Tm Host)

Nekrose

Apoptose

IL-2, IL-12, IFN-y

Perforin

Granzyme A

K/NK

K/NK

TH1

K/NK

Zz+

K/NK

IL-2

TH1

TH1

Nekrose

Apoptose

IL-2, IL-12, IFN-y

Tz

Perforin

Granzyme A

Ag

TH1

Tz

Tz

Zz+

Tz

DC1

IL-2

DC2

IL-1

Neopterin

TH2

Pl

B

Pl

Ts

TH2

TH2

Ak

Pl

-

IL-4

IL-5

IL-6

IL-10

IL-13

+

Komplementlyse

Opsonisierung und ADCC

Phagozytose

TH2

Bm



Immunosuppressive drugs
Immunosuppressive Drugs Host)

  • Antibodies against lymphocytes

    (Anti-CD3, ATG, Anti-CD25)

  • Calcineurin inhibitors

    (Cyclosporine, Tacrolimus [=FK-506])

  • Corticosteroids

  • Antimetabolites (cytotoxic)

    (Azathioprine, Mycophenolate Mofetil)


Anti cd3 anti cd4 anti cd25
Anti-CD3, Anti-CD4, Host)Anti-CD25

  • heterologous monoclonal antibodies against lymphocytes

  • source: mouse

  • Induction of ADCC, apoptosis and blockade of cell function

  • bridging of activated cytotoxic T cells and T helper cells  killing

  • Induction of T suppressor cells


ATG Treatment During Heart Transplantation Host)

350

300

250

200

cells/µl

CD3 (T cellc)

CD16 (NK cells)

CD19 (B cells)

150

100

50

0

-0,5

0

0,5

4

12

24

72

96

Hours before, during and after transplantation



Corticosteroids
Corticosteroids Host)

  • Inhibit IL-1ß and IL-2 synthesis

  • Redistribution of CD4+ lymphocytes from the circulation to other compartments


Mycophenolate mofetil
Mycophenolate Mofetil Host)

  • Inhibits T and B cell proliferation by blocking the production of Guanosin nucleotids for DNA synthesis

  • Inhibits Inosin-Monophosphat-Dehydrogenase (IMP-DH) and thereby production of Guanosin nucleotids for DNA synthesis

  • Specific for IMP-DH-Isoforms in T and B lymphocytes

  • Inhibits glycosylation of adhesion molecules ( Attachment of lymphocytes on endothelium, and  invasion of leucocytes in allograft)


Cyclosporine
Cyclosporine Host)

Daniel et al., Transplantation 2005, 79:1498


Methylprednisolone
Methylprednisolone Host)

Daniel et al., Transplantation 2005, 79:1498


Mycophenolate mofetil1
Mycophenolate mofetil Host)

Daniel et al., Transplantation 2005, 79:1498


Mycophenolate mofetil2
Mycophenolate mofetil Host)

Daniel et al., Transplantation 2005, 79:1498


Plasma il 2
Plasma IL-2 Host)

Daniel et al., Transplantation 2005, 79:1498


Plasma il 10
Plasma IL-10 Host)

Daniel et al., Transplantation 2005, 79:1498


Tm Host)

Necrosis

Apoptosis

X

X

IL2, IL-12, IFN-y

Perforin

Granzyme A

Ciclosporine

K/NK

X

X

X

K/NK

X

X

TH1

K/NK

Zz+

X

K/NK

IL-2

X

TH1

Nekrosis

Apoptosis

Anti-CD3 mAb

Steroids

TH1

X

X

IL-2, IL-12, IFN-y

X

X

Tz

Perforin

Granzyme A

X

Ag

TH1

Tz

X

X

Tz

Zz+

Tz

Mycophenolate

Steroids

Anti-CD3 mAb

Mycophenolate

X

DC1

X

X

IL-2

X

DC2

Steroids

X

X

X

IL-1

Steroids

TH2

Pl

X

X

B

X

Pl

Ts

TH2

TH2

Ak

X

X

Pl

-

IL-4

IL-5

IL-6

IL-10

IL-13

+

Anti-CD3 mAb

TH2

Complement lysis

Opsonization and ADCC

Phagocytosis

Mycophenolate

Mycophenolate

Bm



Transplantation immunology5
Transplantation Immunology Host)

  • TPL (general aspects, numbers, overview, history)

  • HLA

  • Preoperative tests (prophylaxis of rejection)

  • Mechanisms of rejection (solid organs)

  • Immunosuppression

  • Tolerance (induction)

  • Clinical complications (infection, cancer)

  • Bone marrow and stem cell transplantation

  • Xenotransplantation

  • Artifical organs


Rejection of allografts
Rejection of Allografts Host)

  • hyperacute: within minutes

  • acute: 5-9 days posttransplant

  • chronic: lingering for weeks and months





Transplantation immunology6
Transplantation Immunology Host)

  • TPL (general aspects, numbers, overview, history)

  • HLA

  • Preoperative tests (prophylaxis of rejection)

  • Mechanisms of rejection (solid organs)

  • Immunosuppression

  • Tolerance (induction)

  • Clinical complications (infection, cancer)

  • Bone marrow and stem cell transplantation

  • Xenotransplantation

  • Artifical organs


  • Undersuppression

  • acute rejection


Cause of death first cadaver kidney transplant
Cause of Death Host)First Cadaver Kidney Transplant

CTS-Study


Posttransplantation lymphoproliferative disease ptld
Posttransplantation Lymphoproliferative Disease (PTLD) Host)

  • EBV-induced B cell lymphoma; loss of antiviral control due to strong postoperative immunsuppression

  • Reduction or withdrawl of immunsuppressive drugs


Incidence of b cell lymphoma
Incidence of B Cell Lymphoma Host)

  • Normal population: 10/100.000

  • During 1. year after kidney transplantation: 250/100.000

  • During 1. year after heart transplantation: 1.200/100.000


Am J Transplant Host). 2004 Feb;4(2):222-30.

Lymphomas after solid organ transplantation: a collaborative transplant study report.Opelz G, Dohler B.


Figure 1: Ten-year incidence of non-Hodgkin lymphomas (NHLs) in cadaver kidney recipients. Transplants were performed from 1985 to 2001. Expected incidence was based on a nontransplant population of same age and sex distribution and same geographical origin. Relative risk (RR) during the first post-transplant year was 24.6 and yearly RR ranged from 7.3 to 11.2 during the following 9 years.


Lymphocyte subpopulation monitoring
Lymphocyte Subpopulation Monitoring (NHLs) in cadaver kidney recipients.

  • CD3 T lymphocytes

  • CD3/25 activated IL-2R+ T lymphocytes

  • CD3/DR activated HLA-DR+ T lymphocytes

  • CD4 T helper lymphocytes

  • CD4/DR activated HLA-DR+ T helper lymphocytes

  • CD8 suppressor/cytotoxic T lymphocytes

  • CD8/DR activated HLA-DR+ T lymphocytes

  • CD16 natural killer cells

  • CD19 B lymphocytes

  • DR HLA-DR+ monocytes, B lymphocytes, activated T lymphocytes


J Heart Lung Transplant. 2005 Jun;24(6):708-13. (NHLs) in cadaver kidney recipients.

Effectivity of a T-cell-adapted induction therapy with anti-thymocyte globulin (sangstat).Koch A, Daniel V, Dengler TJ, Schnabel PA, Hagl S, Sack FU.Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany; Department of Cardiology, University of Heidelberg, Heidelberg, Germany.BACKGROUND: Cytolytic induction therapy with anti-thymocyte globulin (ATG) should induce effective immunosuppression, with a low rate of rejection in the initial phase after heart transplantation. Induction therapy with ATG allows post-operative renal recovery without the negative effects of highly nephrotoxic cyclosporine levels. An increased rate of infection is a common problem, however, and has been associated with "over-immunosuppression" early after transplantation. Therefore, we investigated whether reduced T-cell-adapted ATG induction therapy could be performed without increasing the risk of graft loss by rejection and whether reductions in infection rates and costs are possible. METHODS: Between March 1999 and December 2002, T-cell-adapted ATG induction therapy with ATG (Sangstat) (1.5 mg/kg) was given to 62 heart transplant recipients (study group) starting on post-operative Days 1 to 6. T-lymphocyte sub-populations were screened daily using flow cytometry. If total lymphocytes were <100/mul (reference 1,300 to 2,300/mul), T-helper lymphocytes (CD4(+)) <50/mul (reference >500/mul) and T-suppressor cells (CD8(+)) <50/mul (reference >300/mul), then no ATG was given. Further immunosuppression was continued with triple therapy consisting of methylprednisolone, azathioprine and cyclosporine. An historic group of heart transplant recipients given a full-dose ATG regimen for 8 days served as controls. These recipients were treated with ATG (Merieux 1.5 mg/kg) until reaching monoclonal cyclosporine levels of >300 mg/dl. Additional immunosuppressive treatment did not differ. Patients in both groups received systemic antibiotics (Imipenem) peri-operatively. Results of routine endomyocardial biopsies and rates of infections were examined. RESULTS: Study group patients were older (52 +/- 10 vs 49 +/- 14 years). In the study group, mean cumulative ATG dose was reduced significantly to 596 +/- 220 mg (p < 0.05) for 3.9 +/- 1.6 days compared with 1,159 +/- 376 mg for 6.9 +/- 1.1 days in the control group. The rate of cytomegalovirus (CMV) seroconversion was 23% in the study group compared with 13% in the control group. Rate of deep sternal infections was lower in the study group (1.6% vs 3.2%). The mean rejection rate in the first 3 months was 0.4 +/- 0.7 for the study patients (185 biopsies) vs 1.1 +/- 1.7 for controls (237 biopsies). All biopsies with ISHLT Grade >2 were treated successfully with 1,000 mg of methylprednisolone intravenously for 3 days. Both groups showed a similar 1-year survival rate (study 88%, control 89%). CONCLUSIONS: T-cell-adapted ATG induction therapy can be a helpful tool for individualized immunosuppression. It is not associated with an increased rate of rejection. Lower doses of immunosuppression help to minimize the rates of infection. In addition, cytolytic induction therapy combined with reduced ATG results in significant cost reduction.


Transplantation immunology7
Transplantation Immunology (NHLs) in cadaver kidney recipients.

  • TPL (general aspects, numbers, overview, history)

  • HLA

  • Preoperative tests (prophylaxis of rejection)

  • Mechanisms of rejection (solid organs)

  • Immunosuppression

  • Tolerance (induction)

  • Clinical complications (infection, cancer)

  • Bone marrow and stem cell transplantation

  • Xenotransplantation

  • Artifical organs


Induction of tolerance
Induction of Tolerance (NHLs) in cadaver kidney recipients.

  • Clonal deletion

  • T suppressor lymphocytes

  • Regulatory T lymphocytes

  • Antiidiotypic antibodies

  • Anergy

  • DC1/DC2

  • Microchimerism

  • Indoleamine 2,3-dioxygenase


Tm (NHLs) in cadaver kidney recipients.

Nekrose

Apoptose

IL-2, IL-12, IFN-y

Perforin

Granzyme A

K/NK

K/NK

TH1

K/NK

Zz+

K/NK

IL-2

TH1

TH1

Nekrose

Apoptose

IL-2, IL-12, IFN-y

Tz

Perforin

Granzyme A

Ag

TH1

Tz

Tz

Zz+

Tz

DC1

IL-2

DC2

IL-1

Neopterin

TH2

Pl

B

Pl

Ts

TH2

TH2

Ak

Pl

-

IL-4

IL-5

IL-6

IL-10

IL-13

+

Komplementlyse

Opsonisierung und ADCC

Phagozytose

TH2

Bm


Mechanism of self tolerance for t cells
Mechanism of Self-Tolerance for T Cells (NHLs) in cadaver kidney recipients.

Central (thymic)

  • lack of positive selection: before CD4-, CD8-

  • clonal deletion: at CD4+, CD8+

  • central clonal anergy: at CD4+ or CD8+


Mechanisms of self tolerance for t cells
Mechanisms of Self-Tolerance for T Cells (NHLs) in cadaver kidney recipients.

Peripheral

clonal deletion: irregular activation

  • crosslinking CD3/TCR with no APC

  • crosslink CD3/TCR and class I together

  • independent crosslinking of CD3/TCR and CD4

    clonal anergy: incompatible activation

  • IL-2 gene silenced

  • IL-2 unresponsiveness

  • low TCR/CD3

  • low CD4/CD8

    immunosuppression: complete activation in the presence of negative regulators

  • nonspecific factors: TGF-ß, Th1-Th2, steroids

  • cognate interactions: idiotypes

    compartmentalization


Am J Transplant (NHLs) in cadaver kidney recipients.. 2005 Apr;5(4 Pt 1):746-56

Evaluation of T-cell receptor repertoires in patients with long-term renal allograft survival.Alvarez CM, Opelz G, Giraldo MC, Pelzl S, Renner F, Weimer R, Schmidt J, Arbelaez M, Garcia LF, Susal C.The mechanisms underlying long-term acceptance of kidney allografts in humans under minimal or no maintenance immunosuppression are poorly understood. We analyzed the T-cell receptor (TCR) repertoires in circulating T cells of patients with long-term (> or = 9 years) renal allograft survival with (LTS-IS) and without immunosuppression (LTS-NoIS). T cells of LTS patients exhibited strongly altered TCR Vss usage, including an increased frequency of oligoclonality and a decreased frequency of polyclonality. All 3 LTS-NoIS and 12 of 16 LTS-IS patients demonstrated oligoclonality in at least three or more TCR V beta families, and the frequency of oligoclonality in these patients was significantly higher as compared to patients with well-functioning grafts at 3 years (p < 0.005 both), an uncomplicated course during the first year (p < 0.0001, both), acute rejection (p < 0.0001, both), chronic allograft nephropathy at 7 (p < 0.0001, both) or 13 years (p < 0.0001, both), dialysis patients (p < 0.0001, both) or healthy controls (p < 0.0001, both). In contrast to LTS patients, all other studied patient groups exhibited a polyclonal TCR repertoire. Our data indicate that TCR alteration is a common feature of long-term allograft outcome, which might be explained by clonal deletion, exhaustion of alloreactive T cells or predominant expression of particular T-cell subpopulations, such as regulatory T cells.


Figure 3: Percentages of (NHLs) in cadaver kidney recipients.oligoclonality in LTS-IS, LTS-NoIS, WF3, UC1, AR, CAN7, CR13 and dialysis patients and healthy controls.*p < 0.05, **p < 0.01, ***p < 0.001. Median, interquartile range (boxes) and range (whiskers) are shown.


J Exp Med. 1973;137:1142-1162 (NHLs) in cadaver kidney recipients.

Identification of a novel cell type in peripheral lymphoid organs of mice.

I. Morphology, quantitation, tissue distribution.Ralph M. Steinman and Zanvil A. Cohn.During the course of observation on the cells of mouse spleen that adhere to glass and plastic surfaces, it was clear that this population was quite heterogeneous. In addition to mononuclear phagocytes, granulocytes, and lymphocytes, we noticed a large stellate cell with distinct properties from the former cell types. In this paper, we describe the morphology, quantitation, and tissue distribution of this novel cell as identified in vitro. In following papers, we will further characterize it with respect to its functional properties in vitro, as well as its localization and properties in situ.


A dendritic cell sensing a lymphocyte (NHLs) in cadaver kidney recipients.Olivier Schwartz, Virus and Immunity Group, Institut Pasteur, Paris, FranceNature Cell Biology 2004; 6(3):188


Mechanisms of graft rejection (NHLs) in cadaver kidney recipients.

Lechler et al. Nat Med. 2005 Jun;11(6):605-13.


Selected strategies for tolerance (NHLs) in cadaver kidney recipients.

induction now in clinical trials.

Lechler et al. Nat Med. 2005 Jun;11(6):605-13.


Kapsenberg m l nat rev immunol 2003 3 984
Kapsenberg, M. L. (NHLs) in cadaver kidney recipients.Nat. Rev. Immunol. 2003; 3:984.


Finding hypothesis i
Finding/Hypothesis I (NHLs) in cadaver kidney recipients.

  • Myeloid DC (DC1) primed T lymphocytes differentiate into effector CD4+ or cytotoxic CD8+ cells mediating allograft rejection (Zou et al. J Immunol 2000; 165:4388)

  • Plasmacytoid DC (DC2) primed T lymphocytes differentiate into regulatory T cells promoting allograft tolerance (Kuwana et al. Eur J Immunol 2001; 31:2547)

  • Rissoan et al., Science 1999; 283:1183

  • Cella et al., Nat Immunol 2000; 1:305


Finding hypothesis ii
Finding/Hypothesis II (NHLs) in cadaver kidney recipients.

Immature DCs induce tolerance whereas mature DCs induce immunity.

Steinman et al. J Exp Med 2000; 191:411

Dhodapkar et al. J Exp Med 2001; 193:233


Finding hypothesis
Finding/Hypothesis (NHLs) in cadaver kidney recipients.

Tolerance results from:

  • T cell deletion

  • T cell silencing

  • Generation of regulatory T cells

Roncarolo et al. J Exp Med 2001; 193:F5

Jonuleit et al. J Exp Med 2000; 192:1213


Generation of tolerogenic regulatory dc
Generation of tolerogenic/regulatory DC (NHLs) in cadaver kidney recipients.

  • Specific culture conditions for propagation of homogenous populations of immature DCs.

  • Pharmacological manipulation of DCs to stabilize their immature/tolerogenic phenotype.

  • Genetic modification of DCs to impair their stimulating ability/enhance their tolerogenicity.

    Raimondi/Thomson; Contrib Nephrol 2005; 146:105


Nat Rev Immunol. 2004 Jan;4(1):24-34 (NHLs) in cadaver kidney recipients..

Dendritic cells: emerging pharmacological targets of immunosuppressive drugs.Hackstein H, Thomson AW.Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig University Giessen, Langhansstr. 7, D-35392 Giessen, Germany. [email protected]


Hackstein and thomson nat rev immunol 2004 4 24
Hackstein and Thomson. (NHLs) in cadaver kidney recipients.Nat. Rev. Immunol. 2004; 4:24.


Transplantation immunology8
Transplantation Immunology (NHLs) in cadaver kidney recipients.

  • TPL (general aspects, numbers, overview, history)

  • HLA

  • Preoperative tests (prophylaxis of rejection)

  • Mechanisms of rejection (solid organs)

  • Immunosuppression

  • Tolerance (induction)

  • Clinical complications (infection, cancer)

  • Bone marrow and stem cell transplantation

  • Xenotransplantation

  • Artifical organs


Problems of xenotransplantation
Problems of Xenotransplantation (NHLs) in cadaver kidney recipients.

  • Natural IgM antinbodies

  • MHC incompatibility

  • PERVs

  • Transfer of virus to human

  • Incompatibility in secrected hormones

  • Cross-reactive antibodies against MHC


Transplantation immunology9
Transplantation Immunology (NHLs) in cadaver kidney recipients.

  • TPL (general aspects, numbers, overview, history)

  • HLA

  • Preoperative tests (prophylaxis of rejection)

  • Mechanisms of rejection (solid organs)

  • Immunosuppression

  • Tolerance (induction)

  • Clinical complications (infection, cancer)

  • Bone marrow and stem cell transplantation

  • Xenotransplantation

  • Artifical organs


Problems of artifical organs
Problems of Artifical Organs (NHLs) in cadaver kidney recipients.

  • Energy supply

  • Blood coagulation

  • Replacing only part of organ functions

  • Immunization of patient

  • Induction of inflammation


Transplantation immunology10
Transplantation Immunology (NHLs) in cadaver kidney recipients.

  • TPL (general aspects, numbers, overview, history)

  • HLA

  • Preoperative tests (prophylaxis of rejection)

  • Mechanisms of rejection (solid organs)

  • Immunosuppression

  • Tolerance (induction)

  • Clinical complications (infection, cancer)

  • Bone marrow and stem cell transplantation

  • Xenotransplantation

  • Artifical organs


Transplantation of
Transplantation of (NHLs) in cadaver kidney recipients.

Bone marrow

  • (from hip, narcosis)

    Blood stem cells

  • (from blood, without narcosis, G-CSF)


Problems of bone marrow transplantation
Problems of Bone Marrow Transplantation (NHLs) in cadaver kidney recipients.

  • HLA-identical donor

  • Graft versus host disease

  • Host versus graft disease (rejection)

  • Infection


Stammzellen
Stammzellen (NHLs) in cadaver kidney recipients.

  • Adulte menschliche Stammzellen: Sie werden aus Organen gewonnen. Das Arbeiten mit Ihnen ist erlaubt, weil dafür keine Embryonen "verwendet" werden. Die Zellen sind jedoch nicht so wandlungsfähig wie die embryonalen Stammzellen.

  • Stammzellen aus Embryonen (ES):Die Zellen können sich in verschiedene Gewebetypen verwandeln. Somit öffnen sich ganz neue Möglichkeiten beispielsweise für die Therapie von Diabetes Mellitus, Alzheimer-Krankheit oder Morbus Parkinson. ES-Zellgewinnung ist jedoch umstritten, weil sie nur aus Embryonen gewonnen werden können. In Deutschland wird zur Zeit aus ethisch-moralischen Gründen darüber diskutiert, ob die deutschen Wissenschaftler für Stammzell Forschung und Gentherapie ES-Zellen aus Israel beziehen dürfen.


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