Chapter 15: Transplantation and Rejection Phenomenon
Transplantation is used to replace an organ that has undergone an irreversible pathological process, which threatens the patient’s life or considerably hampers the quality of life.
Types of Graft
- Autograft: These are 100% successful, with no chances for rejection.
- Isograft Autograft: This is done in the same individual like skin graft or blood: This is between two genetically identical individuals or twins. This is also a successful graft.
The above two grafts survive for an indefinite period of time.
- Allograft(Homograft): This is done between the same species mean man to man, which is the most common procedure e.g. kidney, liver and blood transfusion.
- Xenograft(Heterograft): This is done between two different species like an animal, to man. When in the future if we succeed in this category then various organs will be available commercially.
1997- 158,000 medical patients have end-stage kidney.
1988- 100,000 patients have organ transplantation.
Mid-1989 >18000 were on the waiting list.
Graft Survival in the USA
Kidney = 80-90% (9736 cases)
Liver = 40-50% (3064 cases)
Heart = 70% (2172 cases)
Lung = Low (535 cases)
cornea = 79%
Bone marrow = 80%
Mechanism of Rejection
Rejection is purely an immunologic reaction. The biopsy of the rejected organs invariably shows an inflammatory infiltrate. The analysis of such infiltrate by monoclonal antibodies show the heterogeneous composition of the cellular infiltrate, which consists of. CD4+ cells, CD8+ cells, macrophages, B-lymphocytes and NK cells.
Rejection may be:
- First set rejection or slow rejection which takes 10-14 days.
- The second set of rejection is fast or accelerated rejection.
When mice B grafted first time from mice A then graft is rejected slowly, 10-14 days and this is called first set rejection.
This example also shows that the immune system which produces graft rejection also displays memory and specificity. Because when mice are regrafted from the same donor then graft is rejected more rapidly (6-8 days) and is called Second set rejection. Even if lymphocytes from Mice B when transfused to mice C show second set rejection. But when graft from mice A is put on Mice C again there is First set rejection.
T-Cell Mediated Rejection
Rejection reactions are induced by the recipient Th (CD4+) cells, which recognizes donor MHC-I & II molecules.
Uncommitted recipient CD4+ cells are stimulated by donor Ag and cytokines IL-2 or IL-4 will differentiate CD4+ cells to Th1 or Th2 to initiate a series of immune responses.
Th2 cells mainly secrete IL-4 and IL-10 and initiate Ab production by B-lymphocytes.
Th1 cells secrete IL-2 and IFN-γ which stimulates T-cytotoxic cell (CD8+) and enhance expression of class-I and induce expression of the class-II molecule on donor tissue and activate macrophagic cells.
Activated macrophagic cells release IL-1, TNF-α.
B-Cell Mediated Reaction (Ab Mediated)
There is the main role of T-lymphocytes but B-lymphocytes can also mediate rejection and the possibilities are:
A. Presence of preformed Ab:
- The recipient may have preformed Ab which may take place by giving multiple blood transfusions, pregnancy, and infections. Platelets and white blood cells are rich in HLA-Ag.
- The presence of these preformed Abs gives rise to hyperacute rejection and this may be due to Arthus’ reaction.
- This hyperacute rejection can be avoided by the cross match where we take:-
- Recipient serum + donor lymphocytes are mixed in the culture medium. This procedure called a mixed lymphocyte reaction (MLR) and is the basis for the cross match.
B. Formation of Ab
Exposure of HLA-I & II Ag of donors by the recipient give rise to Ab formation and these may cause damage by:-
- Cytotoxic reaction, ADCC.
- Immune complex disease.
The initial target is graft vasculature and some referred this as rejection vasculitis.
Target Antigen Considered in Transplantation Success
- MHC – major histocompatible antigens called transplantation Ag.
- Minor histocompatibility Ag are H antigens.
- ABO system – this is also very critical for the success of the graft.
- Acute cellular.
- Acute humoral (vasculitis)
|Type||Time after Transplantation||Possible Mechanism|
|Accelerated acute||1-5 days||T-Lymphocytes|
|Acute||From 3rd week||T-Lymphocytes|
|Chronic||Months to year||Ab & C (adhesion molecule)|
Table XXII – Type of Rejections
Hyperacute rejection is due to the presence of preformed Ab in the recipient that is directed against Ag of the donor organs.
Hyperacute rejection can also be mediated by Ab directed against donor HLA-I molecules. The origin of which can be traced to previous leukocytes containing blood transfusion.
This rejection occurs within minutes to hours, so it is recognized by the surgeon at the table, particularly in case of kidney transplant.
The kidney will be cyanotic, mottled and flaccid.
Few drops of urine will form and these may be bloody.
Microscopic Examination of graft tissue (kidney) shows:
- There is Interstitial edema.
- Infiltration by neutrophils around blood vessels, glomeruli, and peritubular capillaries.
- Intravenous fibrin- platelet thrombi may be seen.
- There is fibrinoid necrosis of arterioles.
- Classically there is Arthus reaction.
- Deposition of Ig and complement may be demonstrated in the blood vessels.
The kidney cortex undergoes infarction, then necrosis and end result is the non-functioning kidney.
Acute Rejection can occur within day or suddenly, in months or years accompanied by signs and symptoms of renal failure.
Signs and Symptoms
- Patient will have fever and chills.
- There is oliguria.
- There is swollen graft.
Acute rejection usually occurs after stopping immunosuppressive therapy.
Acute Rejection may be due to :
- T-L (cell-mediated immunity).
- B-L (Humoral).
Morphologically acute rejection is of two types:
- Humoral (Vasculitis).
- b. Cell-mediated (acute cellular).
A. Acute Cellular Rejection
This is cell-mediated due to T-L. It occurs in initial months and the patient develops abrupt sign/symptoms of renal failure.
There is edema, mononuclear cellular infiltrate of T-L (CD4+, CD8+ and macrophages). There may be mild hemorrhage and focal tubular necrosis. But there is no evidence of vasculitis.
This acute cellular rejection can be treated by giving cyclosporin and there will be a prompt response.
B. Acute (Humoral) Vasculitis
This occurs in the first ten months or when immunosuppressive therapy is stopped.
There is predominantly necrotizing vasculitis.
There is infiltration of neutrophils and formation of fibrin thrombi. There is necrosis of glomeruli and cortical arterial thrombosis. The presence of Ig and complement can be demonstrated.
There is no response to increasing doses of immunosuppressive therapy. This is the reason that on biopsy this should be separated and diagnosed.
Subacute Rejection (Vasculitis)
This also occurs in first few months and this is common condition.
The patient will have altered renal function suggesting an episode of rejection.
Microscopically main changes are:
- These are mainly in the intima. There are proliferation and thickening of the intima.
- There is the proliferation of fibroblasts, myocytes and foamy macrophages, leading to luminal narrowing.
- There may be infiltrating of neutrophils and mononuclear phagocytic cells.
Walls of these arteries show the deposition of Ig and complement.
Chronic Rejection will be followed by a steadily increasing level of creatinine over a period of 4-6 months.
Chronic rejection appears after months or years of successful transplantation. It is a major cause of long term graft loss, but its pathophysiology is poorly understood.
Microscopically the changes are mainly vascular which may be early damage to the endothelium.
- There is diffuse intimal fibrosis particularly in cortical arteries. This will lead to ischemia and changes in the glomeruli.
- There is tubular atrophy and interstitial fibrosis further leads to a decrease in renal parenchyma.
- Cell infiltrate is not a major feature of chronic rejection, although macrophages play an important role through cytokines release (IL-1, IL-6 and TNF-a).
- There is the presence of mononuclear phagocytes, plasma cells, lymphocytes and eosinophil.
Methods Increasing Graft Survival
- ABO blood group compatibility is the most important factor.
- HLA tissue typing–Minimizing HLA disparity of donor and recipient leads to successful transplantation.
- When donor/recipient HLA types are matching, the successful survival is 70% but when these are mismatched then survival of the graft is low.
- Cadaveric kidney survival for 5 years is 33.50% but this may be more in living relatives donated organs.
- Cross-matching of recipient serum with donors lymphocytes prevents hyperacute rejection due to preformed Abs.
Post Operative Therapy
- All transplanted recipients need immunosuppressive treatment except in identical twins.
- Corticosteroids are given for maintenance therapy or bolus at time of rejection. These are anti-inflammatory and decrease the number of circulating lymphocytes. These also interfere with production of lymphokines; Down regulate the expression of cytokine genes like IL1, 2, 3,4,5,8, TNFa and GM-CSF.
- Antimetabolites and Alkylating agents:- These control DNA & RNA functions and leads to the death of rapidly dividing lymphocytes e.g. Azathioprin and Cyclophosphamide.
- Cyclosporin:- These are cyclic peptide antibiotic produced by fungi. These are varying effective in inhibiting T-L.
- Anti-Lymphocytes globulin and anti-thymocyte globulin can destroy T-Lymphocytes.
Complication of Post Operative Therapy
- These patients are prone to develop infection and 25% die due to sepsis in the kidney.
- 6% develops malignancy like skin cancers and 50% lymphoma or sarcomas.
Transplantation of Hemopoietic Cells (B M Transplantation)
Bone marrow transplantation is done in:
- Hematological malignancies like leukemia.
- Aplastic anemia.
- Certain immune deficiency status.
Before marrow is transplanted from the donor and the recipient is radiated with a lethal dose to destroy malignant cells or create an aplastic condition.
A major problem of Bone Marrow transplantation and occasionally in the liver are:
- Transplant rejection.
- Graft VS host disease (GVD).
Mechanism of Graft VS Host disease
This immunological condition arises when graft contains immunocompetent cells are engrafted into an immunologically incompetent recipient. Immuno-competent cells of the graft recognize Ag (alloantigen) of the recipient and are activated. When GVH becomes symptomatic the term graft versus host disease (GVHD) is a more appropriate name. Donors (immune cells) recognize recipient HLA – Ag as foreign and reacts against them with sensitization and anti-recipient CD4+ and anti-recipient CD8+ are generated.
Donors CD4+ and CD8+ are Activated against recipient HLA Ag (Class-I Molecule and Class-II Molecule).
Donors immune cells (CD4+ and CD8+) → Recognise recipient HLA-Ag (Class-I & II) Molecule.
Graft versus Host disease is of two types:
- Acute disease (Acute GVHD).
- Chronic disease (Chronic GVHD).
It occurs in the first 1-2 months after transplantation.
Any organ may be involved and the main problem is due to involvements of the immune system and epithelium of skin, liver, and intestine.
Infections are very common.
Signs and Symptoms
- Skin shows generalized rashes.
- Liver: – There is bile duct destruction and the patient develops jaundice.
- Intestine: – There is mucosal ulceration of gut and patients may develop bloody diarrhea.
It appears after at least 2-3 months after transplantation.
This may follow acute or insidious onset.
Signs and Symptoms
- There is extensive cutaneous injury and maybe fibrosis in the dermis. There are desquamation and blister formation.
- The liver shows chronic liver disease like cholestatic jaundice and alkaline phosphates level is raised.
- Gastrointestinal tract:- The patient may have abdominal pain and diarrhea with life-threatening electrolytes imbalance. There may be esophageal stricture.
- Recurrent infections are also common.
The most effective treatment to prevent acute GVHD is a combination of methotrexate and cyclosporin. While treatment of established GVHD is with methylprednisolone, cyclosporin and or anti-thymocyte globulin.
If donor T lymphocytes from bone marrow are depleted then GVHD will be prevented.