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Figure 1.

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Table 1.

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(4)
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Figure 4

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Figure 5

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Figure 6.

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Figure 7.

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Figure 8

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Figure 10

. Schematic representation of immunopathophysiology of GVHD. In phase 1, the conditioning regimen (irradiation, chemotherapy, or both) leads to the damage and activation of host tissues. This allows stimulation of macrophages and APC, followed in phase 2 by Donor T-cell activation and expansion. In phase 3, effector functions of activated mononuclear phagocytes are triggered by the secondary signal provided by LPS and other immuno- stimulatory molecules that leak through the intestinal mucosa damaged during phases 1 and 2. This damage results in the amplification of local tissue injury, and it further promotes an inflammatory response.

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(13)

Paczesny S, Bone Marrow Transplantation 2010

Figure 12.

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Figure 13.

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Figure 14.

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Table 2.

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Figure 15.

A

B

(18)

GROUPE C1 (KIR2DL2/3) GROUPE C2 (KIR2DL1)

HLA-Cw1 HLA-Cw2

HLA-Cw3 all except C0307, C0310, C0315 HLA-C0307, HLA-C0310, HLA-C0315 HLA-Cw7 all except C0707, C0709 HLA-Cw4

HLA-Cw8 HLA-Cw5

HLA-Cw12 all except C1205, C12041, C12042 HLA-Cw6

HLA-Cw13 HLA-C0707, C0709,

HLA-Cw14 all except C1404 HLA-C1205, HLA-C12041, HLA-C12042

HLA-C1507 HLA-Cw15 except HLA-C1507

HLA-Cw16 all except C1602 HLA-Cw1602

HLA-Cw17 HLA-Cw18

HLA-C alleles specificity for the two Inhibitory receptors

Table 3 A and B.

Figure 16

HLA-Bw4 supertypic family corresponding to HLA-B*05, B*13, B*17, B*27, B*37, B*38, B*44, B*47, B*49, B*51, B*52, B*53, B*57, B*58, B*59, B*63, B*77,

B*1513, B*1516, B*1517, B*1523, B*1524)

HLA-A alleles (HLA-A*03, A*11, A*23, A*24, A*25, A*32[h1]).

KIR characterized by three Ig-like domains (KIR3D) are specific for HLA-Bw4 supertypic family or for certain HLA-A alleles

A

B

(19)

Table 4.

(20)

Figure 17.

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(22)

Figure 19.

Adaptedfrom anaximperator.files.wordpress.com

DC

DC VACCINEVACCINE

What antigen format for cellular vaccine?

Peptides : Synthetic Acid Eluted

MHC-Purified

Proteins: Recombinant Cell lysate

Genetic: RNA DNA Fusions Peptides : Synthetic

Acid Eluted MHC-Purified

Proteins: Recombinant Cell lysate

Genetic: RNA DNA Fusions

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Figure 20.

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Figure 21.

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Figure 22.

Antigen specific Donor Lymphocyte Infusion

(26)

Figure 23

Post Transplant Vaccination

(27)

TABLE 5

(28)

Figure 24.

(29)

Figure 25.

B

A

(30)

Figure 26. Immune reconstitution (CD4 (A), CD8 (B), CD56 (C) lymphocytes) measured by Flow cytometry absolute lymphocyte count, comparison between the control cohort and the GCSF + DLI cohort

A

B

C

(31)

Figure 27. Real-time quantitative PCR for the detection of minimal

residual disease in an acute lymphoblastic leukemia patient, using

patient specific junctional region of rearranged immunoglobulin gene

TaqMan probes, after haploidentical transplant. Response of the

minimal residual disease to Donor Lymphocyte Infusion (DLI)

(32)

Figure 28. Immune reconstitution (CD4 (A), CD8 (B), CD56 (C) lymphocytes) measured by Flow cytometry absolute lymphocyte count, comparison between the control cohort and the GMCSF + DLI cohort

A

B

C

(33)

Figure 29.

Example of the impact of one DLI after GMCSF on the lymphocyte absolute count (CD4+ T cells): Drastic increase of CD4+ T cells, provoking aGVHD and requesting high dose steroids treatment, new drop of lymphocyte count under steroids and recovery of the lymphocytes count after the end of the steroids treatment

GVHD

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Figure 30. Immune reconstitution (CD4 (A), CD8 (B), CD56 (C) lymphocytes) measured by Flow cytometry absolute lymphocyte count, comparison between the control cohort and the GMCSF cohort

A

B

C

(35)

Figure 31. Anti-CMV lymphocytes generation for

adoptive T cell transfer

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Figure 32.

Immature dendritic cells were loaded with CMV antigen positive cell lysate (1 mg/ml) and then used irradiated. PBMCs were used as responders cells in a three weeks primary MLR. On day 21, T lymphocytes (CD4-positive and CD8-positive) were assessed for intracytoplasmic detection of INFg by flow cytometry in order to analyze the capacity of the DCs to prime CMV-specific type-1 T cell response. The controls consisted of T cells with control lysate loaded DCs.

Data represent individual percentage of T cells secreting INFg for the 23 patients.

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Patient 1 Patient 2

Patient 3 Patient 4

Patient 5 Patient 6

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Patient 7 Patient 8

Patient 9

Figure 33. Individual clinical follow up of 9 patients receiving CMV-specific T cells infusion (1X10

4

total cultured cell/Kg) as anti-CMV prophylactic or

preemptive treatment.

(39)

Figure 34. Anti-leukemic lymphocytes generation for

adoptive T cell transfer

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TABLE 6: DCs gener ated and m atured in plates, pla-DCs (line 1), showed a higher percentage of CD80 positive cells compared to b ag-DCs (line 2). Their median fluorescence intensity (MFI) for CD80, CD86, HLA-DR and CD40, was also significantly higher. The results were similar when the DCs were generated from CD14+ purified monocytes (line 5 compared to line 6). The cross-over of DCs, generated in Bags and Plates, for maturation showed intermediate percentage and median intensity without reaching statistical significance when compared either to pla- DCs or bag- DCs. (line 3 and 4).

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Figure 35

Figure 35.

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Figure 36

Figure 36.

Infγ product ion upon HIVgp41-antigen stimulation. Pla-DCs (A, B) or bag-DCs (C, D) were loaded with HIVgp41 protein (25 µg/ml) and then used irradiated, immature or after 12h and 48h maturation.

PBMCs were use d as respo nders cells in a thr ee weeks primary MLR with or without exogenous recombinant IL12. On day 21, T lymphocytes (CD4-positive on panel A and C, and CD8-positive on panel B and D) were assessed for intracytoplasmic detection of INF by flow cytometry in order to analyze the capacity of the DCs to prime Ag-specific type-1 T cell res ponse. Controls consisted of T cells alone, DCs alone, and T cells on unloaded DCs.

Data represent percentage of T cells secreting INF .

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Table 7

TABLE 7.

Table 8.

Table 9

TABLE 8 and 9.

(44)

Figure 37 Figure 38

Figure 39

Figure 37 . Figure 38.

Figure 39.

(45)

Table 10

Table 11

Table 10.

Table 11.

(46)

Figure 40.

Immature dendritic cells were loaded with WT1 human recombinant protein, or with pp65 CMV protein or GP41 HIV protein (50 μg/ml) as control antigens for two volunteers. After 4hours loading, the DC were matured with the maturation cocktail (IL- 1,TNFα, INFα, INFγ, PIC) during 24h. PBMCs were used as responders cells in a three weeks MLR. MLR was extended to 4 weeks for two MLR (1and 2) of the second volunteer. (Extension of the MLR to 4 weeks didn’t consistently improve the results) On day 21 or 28, T lymphocytes (CD4-positive and CD8-positive) were assessed for intracytoplasmic detection of INFg by flow cytometry in order to analyze the capacity of the DC to prime WT1-specific type-1 T cell response. CMV and/or HIV antigen were used as control (subtracted background consisted of T cells with unloaded DC). Data represent individual percentage of T cells secreting INFg for 4 healthy individuals. MLR were repeated 1 to 4 times depending of the cells availability of each volunteer to assess reproducibility.

(47)

Figure 41.

Preliminary data on one healthy volunteer to test the impact of CD25+ T cell depletion on antigen specific response Immature dendritic cells were loaded with WT1 human recombinant protein, or with pp65 CMV protein or GP41 HIV protein (50μg/ml) as control antigens. After 4hours loading, the DC were matured with the maturation cocktail (IL-1,TNFα, INFα, INFγ, PIC) during 24h. Total CD3+ T cells or CD25+ depleted CD3+ T cells were used as responders cells in a three weeks MLR. On day 21, T lymphocytes were assessed for intracytoplasmic detection of INFg by flow cytometry in order to analyze the capacity of the DC to prime WT1- specific type-1 T cell response and the impact of CD25+ depletion on this capacity. CMV and/or HIV antigen were used as control (subtracted background consisted of T cells with unloaded DC).

Data represent percentage of T cells secreting INFg in one healthy individuals.

(48)

Figure. 43 a and b

Courtesy of Kiadis Pharma

A

B

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(50)

Molecular Basis of Antigen Recognition

Figure 42

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