steps in T-Cell–Mediated Rejection.

Antigen-presenting cells of host or donor origin migrate to T-cell areas

of secondary lymphoid organs. These T cells ordinarily circulate
between lymphoid tissues, regulated by chemokine and sphingosine-1-
phosphate (S-1-P) receptors.4 APCs present donor antigen to naive
and central memory T cells. Some presentation of antigen by donor
cells in the graft cannot be excluded (e.g., endothelial cells that
activate antigen-experienced T cells). T cells are activated and
undergo clonal expansion and differentiation to express effector
functions.
Antigen triggers T-cell receptors (TCRs) (signal 1) and synapse
formation.5 CD80 (B7-1) and CD86 (B7-2) on the APC engage CD28
on the T cell to provide signal 2.
These signals activate three signal-transduction pathways

1. the calcium–calcineurin pathway,

2. the mitogen-activated protein (MAP) kinase pathway, and
3. the protein kinase C–nuclear factor-kappa B (NF-kappa B)
pathway —

which activate transcription factors nuclear factor of activated T cells

(NFAT), activating protein 1 (AP-1), and NF-kappa B, respectively.

Azathiprine

 derived from 6-mercaptopurine

 thought to act by releasing 6-mercaptopurine, which interferes
with DNA synthesis
 other possible mechanisms include converting costimulation into
an apoptotic signal
 currently second line drug

Calcinuerin inhibitors
Cyclosporine

 a prodrug that engages cyclophilin, an intracellular protein of

the immunophilin family, forming a complex that then engages
calcineurin
 adverse effects related to concentration of the drug include,
nephrotoxicity, hypertension, hyperlipidemia, gingival
hyperplasia, hirsutism and tremor
 can induce haemolytic-uremic syndrome and post
transplantation diagetes mellitus
 monitor of peak cyclosporine levels 2 hours after administration

Tacrolimus

 engases another immunophilin, FK506-binding protein 12

(FKBP12) to create a complex that inhibits calcineurin
 nephrotoxicity and hemolytc uremic syndrome
 less likely to cause hyperlipidemia, hypertension and cosmetic
problems
 more likely to cause post transplantation diabetes
Inosine Monophosphate Dehydrogenase Inhibitors
Mycophenolate

 mcophenolate mofetil is a prodrug that releases mycophenolic

acid
 inhibitor of purine synthesis
 protocols using mycophenolate mofetil and calcineurin inhibitors
improved patient survival and graft survival and reduced early
and late allograft rejection
 largely replaced azathiprine
 simple to use without monitoring and free from organ toxicity
and cardiovascular risk
 toxic effects: GI mainly diarrhoea and haematological anaemia
and leukopenia, increased CMV disease

Target-of Rapamycin Inhibitors

Sirolimus and everolimus

 inhibit target of rapamycin (do not inhibit calcineurin) resulting

in preventing cytokine receptors from activating the cell cycle
 SE: hyperlipidemia, thrombocytopenia and impaired wound
healing – others include:delayed recoverey from actue tubular
necrosis in kidney transplants, reduced testosterone
concentrations, aggravation of proteinuria, mouth ulcers, skin
lesions and pneumonitis
 May reduce CMV
HSCT : BM transplant..
T-cell activation inhibitors orT cell signal inhibitors : antigen presenting cells
present foreign antigens to T cell receptors of hosts leading to signal 1 activation -
 signal 2 and 3 activation  T cell activation and expansion  graft rejection:
Calcineurin inhibitros like Tacrolimus/Cycloporine block signal 1 path and mTOR
inhibitors like sacrolimus/everolimus block signal 3 . Antimitotic drugs or purine
RNA/DNA inhibitors are MM Azathioprine. T Cell signal blockers are used in
combination with antimitotic and prednisone due to different MOA. With OI lower
or stop Prednisone then antimitotics due to BM suppression and neutropenia.

1-T-CELL signal blockers:

-Calcineurin Inhibitor : Tacrolimus/cyclosporins:

.Prograf-Tacrolimus-check levelsl: Usually used universally with MM and

Prednisone
Renal Failure /Tremors/ burning due to neuropathy / Hypertension / high
cholerstrol DM. Voriconazole increases levels of TAC so miss one dose of Tac and
then reduce by 50% while on Vori and check levels .

.Gengraft or Cyclosporin – for lung transplan – check levels:

Renal Failure / Hirsutism/HTN / Neuropathy --stronger more toxic then above ?

-mTOR inhibitors: Sacrolimus/everolimus:

Less effective than Tacro/cyclo less side effects – MC SE impaired wound healing
start after wound healed.

2-DNA/RNA inhibitors ( Replication inhibitors ):

--Celcept- Mycofenolate Moftil : IMP blocker leading to purine synthesis blockade
and blockade of cell immune cell division .

SE: BM suppression NP anemia - Diarrhea – CMV disease

--Imuran or Azathioprine:
DNA blocker.
Diarrhea / BM suppression.

3- Steroids:
PREDNISONE:
Used in combination with T-cell signal inhibitors – DNA/RNA inhibitors

Combine : Caclineurin Inhibitor or mTOR inhibitor with MM or Azathia and

prednisone..
ADENO – virus infection: Presents with conjunctivitis - respiratory tract infection –
hepatitis – enterocolitis – hmgic cystitis -- > diagnose with PCRs – tissue immune
staining and cultures. Treat with lipophilic Cidofovir and reduction of IS.

HHV-6 : Presents with Encehpalitis / pneumonitis / hepatitis / infectious mono like

syndrome with soar throat -LA – oral ulcers – rash – diagnose with PCRS.